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Pinco P, Facciotti F. Unconventional T Cells' Role in Cancer: Unlocking Their Hidden Potential to Guide Tumor Immunity and Therapy. Cells 2025; 14:720. [PMID: 40422223 DOI: 10.3390/cells14100720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 04/24/2025] [Accepted: 05/13/2025] [Indexed: 05/28/2025] Open
Abstract
Unconventional T (UC T) cells, including invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, γδ T cells, and double-negative (DN) T cells, are key players in immune surveillance and response due to their properties combining innate-like and adaptive-like features. These cells are widely present in mucosal tissues, where they can rapidly respond to infections and tumor-associated changes. In fact, UC T cells can have both pro- and anti-tumoral effects, with their activity influenced by factors such as microbial composition and the tumor microenvironment. In particular, intratumoral microbiota significantly impacts the development, function, and activation of UC T cells, influencing cytokine production and shaping the immune response in various cancers. The complex crosstalk between UC T cells and the surrounding factors is discussed in this review, with a focus on how these cells might be interesting candidates to explore and exploit as anticancer therapeutic agents. However, the great potential of UC T cells, not only demonstrated in the context of adoptive cell transfer, but also enhanced through techniques of engineering, is still flanked by different challenges, like the immunosuppressive tumor microenvironment and heterogeneity of target molecules associated with some specific categories of tumors, like gastrointestinal cancers.
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Affiliation(s)
- Paola Pinco
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
| | - Federica Facciotti
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
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2
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Li YR, Shen X, Zhu Y, Lyu Z, Yang L. The microbiota shapes the life trajectory of mucosal-associated invariant T cells. Trends Microbiol 2025:S0966-842X(25)00107-6. [PMID: 40280795 DOI: 10.1016/j.tim.2025.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 03/21/2025] [Accepted: 03/25/2025] [Indexed: 04/29/2025]
Abstract
Mucosal-associated invariant T (MAIT) cells are innate-like T cells predominantly located in barrier tissues such as the lung, liver, skin, and colon. These cells recognize metabolites derived from the riboflavin biosynthetic pathway, which can rapidly traverse epithelial barriers and be presented during MAIT cell differentiation in the thymus and maturation in peripheral tissues. Furthermore, microbial metabolites significantly influence MAIT cell functions in various conditions, including cancer. This review summarizes how the microbiota shapes the life trajectory of MAIT cells and their antitumor reactivity. Additionally, we discuss the therapeutic implications of manipulating the microbiota as a 'bug-drug' strategy to enhance MAIT cell antitumor immunity, particularly in mucosal cancers, while emphasizing challenges and future directions for integrating microbiota considerations into MAIT cell-based therapies.
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Affiliation(s)
- Yan-Ruide Li
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA.
| | - Xinyuan Shen
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Yichen Zhu
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Zibai Lyu
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Lili Yang
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, Los Angeles, CA 90095, USA; Goodman-Luskin Microbiome Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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3
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Lewinsohn DA, Kain D, Awad W, McElfresh GW, Cansler M, Swarbrick G, Poa K, McNeice C, Boggy G, Rott K, Null M, Lewinsohn D, Rossjohn J, Bimber B. Human Neonatal MR1T Cells Have Diverse TCR Usage, are Less Cytotoxic and are Unable to Respond to Many Common Childhood Pathogens. RESEARCH SQUARE 2025:rs.3.rs-6265058. [PMID: 40235492 PMCID: PMC11998791 DOI: 10.21203/rs.3.rs-6265058/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Neonatal sepsis is a leading cause of childhood mortality. Understanding immune cell development can inform strategies to combat this. MR1-restricted T (MR1T) cells can be defined by their recognition of small molecules derived from microbes, self, and drug and drug-like molecules, presented by the MHC class 1-related molecule (MR1). In healthy adults, the majority of MR1T cells express an invariant α-chain; TRAV1-2/TRAJ33/12/20 and are referred to as mucosal-associated invariant T (MAIT) cells. Neonatal MR1T cells isolated from cord blood (CB) demonstrate more diversity in MR1T TCR usage, with the majority of MR1-5-OP-RU-tetramer(+) cells being TRAV1-2(-). To better understand this diversity, we performed single-cell-RNA-seq/TCR-seq (scRNA-seq/scTCR-seq) on MR1-5-OP-RU-tetramer(+) cells from CB (n=5) and adult participants (n=5). CB-derived MR1T cells demonstrate a less cytotoxic/pro-inflammatory phenotype, and a more diverse TCR repertoire. A panel of CB and adult MAIT and TRAV1-2(-) MR1T cell clones were generated, and CB-derived clones were unable to recognize several common riboflavin-producing childhood pathogens (S. aureus, S. pneumoniae, M. tuberculosis). Biochemical and structural investigation of one CB MAIT TCR (CB964 A2; TRAV1-2/TRBV6-2) showed a reduction in binding affinity toward the canonical MR1-antigen, 5-OP-RU, compared to adult MAIT TCRs that correlated with differences in β-chain contribution in the TCR-MR1 interface. Overall, this data shows that CB MAIT and TRAV1-2(-) MR1T cells, express a diverse TCR repertoire, a more restricted childhood pathogen recognition profile and diminished cytotoxic and pro-inflammatory capacity. Understanding this diversity, along with the functional ability of TRAV1-2(-) MR1T cells, could provide insight into increased neonatal susceptibility to infections.
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Abstract
Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved T cells that recognize microbial metabolites. They are abundant in humans and conserved during mammalian evolution, which suggests that they have important nonredundant functions. In this article, we discuss the evolutionary conservation of MAIT cells and describe their original developmental process. MAIT cells exert a wide variety of effector functions, from killing infected cells and promoting inflammation to repairing tissues. We provide insights into these functions and discuss how they result from the context of stimulation encountered by MAIT cells in different tissues and pathological settings. We describe how MAIT cell numbers and features are modified in disease states, focusing mainly on in vivo models. Lastly, we discuss emerging strategies to manipulate MAIT cells for therapeutic purposes.
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Affiliation(s)
- Marion Salou
- Immunity and Cancer, INSERM U932, PSL University, Institut Curie, Paris, France; , ,
| | - Rafael A Paiva
- Immunity and Cancer, INSERM U932, PSL University, Institut Curie, Paris, France; , ,
| | - Olivier Lantz
- Immunity and Cancer, INSERM U932, PSL University, Institut Curie, Paris, France; , ,
- Laboratoire d'Immunologie Clinique, Institut Curie, Paris, France
- Centre d'Investigation Clinique en Biothérapie, Gustave-Roussy and Institut Curie (CIC-BT1428), Paris, France
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5
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Kain D, Awad W, McElfresh GW, Cansler M, Swarbrick GM, Poa KCY, McNeice C, Boggy G, Rott K, Null MD, Lewinsohn DM, Rossjohn J, Bimber BN, Lewinsohn DA. Human Neonatal MR1T Cells Have Diverse TCR Usage, are Less Cytotoxic and are Unable to Respond to Many Common Childhood Pathogens. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.17.643805. [PMID: 40166301 PMCID: PMC11956999 DOI: 10.1101/2025.03.17.643805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Neonatal sepsis is a leading cause of childhood mortality. Understanding immune cell development can inform strategies to combat this. MR1-restricted T (MR1T) cells can be defined by their recognition of small molecules derived from microbes, self, and drug and drug-like molecules, presented by the MHC class 1-related molecule (MR1). In healthy adults, the majority of MR1T cells express an invariant α-chain; TRAV1-2/TRAJ33/12/20 and are referred to as mucosal-associated invariant T (MAIT) cells. Neonatal MR1T cells isolated from cord blood (CB) demonstrate more diversity in MR1T TCR usage, with the majority of MR1-5-OP-RU-tetramer(+) cells being TRAV1-2(-). To better understand this diversity, we performed single-cell-RNA-seq/TCR-seq (scRNA-seq/scTCR-seq) on MR1-5-OP-RU-tetramer(+) cells from CB (n=5) and adult participants (n=5). CB-derived MR1T cells demonstrate a less cytotoxic/pro-inflammatory phenotype, and a more diverse TCR repertoire. A panel of CB and adult MAIT and TRAV1-2(-) MR1T cell clones were generated, and CB-derived clones were unable to recognize several common riboflavin-producing childhood pathogens (S. aureus, S. pneumoniae, M. tuberculosis). Biochemical and structural investigation of one CB MAIT TCR (CB964 A2; TRAV1-2/TRBV6-2) showed a reduction in binding affinity toward the canonical MR1-antigen, 5-OP-RU, compared to adult MAIT TCRs that correlated with differences in β-chain contribution in the TCR-MR1 interface. Overall, this data shows that CB MAIT and TRAV1-2(-) MR1T cells, express a diverse TCR repertoire, a more restricted childhood pathogen recognition profile and diminished cytotoxic and pro-inflammatory capacity. Understanding this diversity, along with the functional ability of TRAV1-2(-) MR1T cells, could provide insight into increased neonatal susceptibility to infections.
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Affiliation(s)
- Dylan Kain
- Division of Infectious Diseases, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Oregon Health & Science University, Portland, OR, USA
- Division of Infectious Diseases,Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Wael Awad
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - G W McElfresh
- Oregon National Primate Research Center, OHSU, Beaverton, OR, USA
| | - Meghan Cansler
- Division of Infectious Diseases, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA
| | - Gwendolyn M Swarbrick
- Division of Infectious Diseases, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA
| | - Kean Chan Yew Poa
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Conor McNeice
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Gregory Boggy
- Oregon National Primate Research Center, OHSU, Beaverton, OR, USA
| | - Katherine Rott
- Division of Infectious Diseases, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA
| | - Megan D Null
- Division of Infectious Diseases, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA
| | - David M Lewinsohn
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Oregon Health & Science University, Portland, OR, USA
| | - Jamie Rossjohn
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff, UK
| | - Benjamin N Bimber
- Oregon National Primate Research Center, OHSU, Beaverton, OR, USA
- Vaccine and Gene Therapy Institute, OHSU, Beaverton, OR, USA
| | - Deborah A Lewinsohn
- Division of Infectious Diseases, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA
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6
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Tang MH, Ligthart I, Varga S, Lebeer S, van Overveld FJ, Rijkers GT. Mutual Interactions Between Microbiota and the Human Immune System During the First 1000 Days of Life. BIOLOGY 2025; 14:299. [PMID: 40136555 PMCID: PMC11940030 DOI: 10.3390/biology14030299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 02/25/2025] [Accepted: 03/14/2025] [Indexed: 03/27/2025]
Abstract
The development of the human immune system starts during the fetal period in a largely, but probably not completely, sterile environment. During and after birth, the immune system is exposed to an increasingly complex microbiota. The first microbiota encountered during passage through the birth canal colonize the infant gut and induce the tolerance of the immune system. Transplacentally derived maternal IgG as well as IgA from breast milk protect the infant from infections during the first 100 days, during which the immune system further develops and immunological memory is formed. The Weaning and introduction of solid food expose the immune system to novel (food) antigens and allow for other microbiota to colonize. The cells and molecules involved in the mutual and intricate interactions between microbiota and the developing immune system are now beginning to be recognized. These include bacterial components such as polysaccharide A from Bacteroides fragilis, as well as bacterial metabolites such as the short-chain fatty acid butyrate, indole-3-aldehyde, and indole-3-propionic acid. All these, and probably more, bacterial metabolites have specific immunoregulatory functions which shape the development of the human immune system during the first 1000 days of life.
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Affiliation(s)
- Muy Heang Tang
- Department of Science and Engineering, University College Roosevelt, 4331 CB Middelburg, The Netherlands; (M.H.T.); (I.L.); (S.V.); (F.J.v.O.)
| | - Ishbel Ligthart
- Department of Science and Engineering, University College Roosevelt, 4331 CB Middelburg, The Netherlands; (M.H.T.); (I.L.); (S.V.); (F.J.v.O.)
| | - Samuel Varga
- Department of Science and Engineering, University College Roosevelt, 4331 CB Middelburg, The Netherlands; (M.H.T.); (I.L.); (S.V.); (F.J.v.O.)
| | - Sarah Lebeer
- Lab of Applied Microbiology and Biotechnology, Department of Bioscience Engineering, University of Antwerp, 2020 Antwerpen, Belgium;
| | - Frans J. van Overveld
- Department of Science and Engineering, University College Roosevelt, 4331 CB Middelburg, The Netherlands; (M.H.T.); (I.L.); (S.V.); (F.J.v.O.)
| | - Ger T. Rijkers
- Department of Science and Engineering, University College Roosevelt, 4331 CB Middelburg, The Netherlands; (M.H.T.); (I.L.); (S.V.); (F.J.v.O.)
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7
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Wu Z, Chen X, Han F, Leeansyah E. MAIT cell homing in intestinal homeostasis and inflammation. SCIENCE ADVANCES 2025; 11:eadu4172. [PMID: 39919191 PMCID: PMC11804934 DOI: 10.1126/sciadv.adu4172] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 01/08/2025] [Indexed: 02/09/2025]
Abstract
Mucosa-associated invariant T (MAIT) cells are a large population of unconventional T cells widely distributed in the human gastrointestinal tract. Their homing to the gut is central to maintaining mucosal homeostasis and immunity. This review discusses the potential mechanisms that guide MAIT cells to the intestinal mucosa during homeostasis and inflammation, emphasizing the roles of chemokines, chemokine receptors, and tissue adhesion molecules. The potential influence of the gut microbiota on MAIT cell homing to different regions of the human gut is also discussed. Last, we introduce how organoid technology offers a potentially valuable approach to advance our understanding of MAIT cell tissue homing by providing a more physiologically relevant model that mimics the human gut tissue. These models may enable a detailed investigation of the gut-specific homing mechanisms of MAIT cells. By understanding the regulation of MAIT cell homing to the human gut, potential avenues for therapeutic interventions targeting gut inflammatory conditions such as inflammatory bowel diseases (IBD) may emerge.
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Affiliation(s)
- Zhengyu Wu
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Xingchi Chen
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Fei Han
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Edwin Leeansyah
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
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8
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Lagattuta KA, Kohlgruber AC, Abdelfattah NS, Nathan A, Rumker L, Birnbaum ME, Elledge SJ, Raychaudhuri S. The T cell receptor sequence influences the likelihood of T cell memory formation. Cell Rep 2025; 44:115098. [PMID: 39731734 PMCID: PMC11785489 DOI: 10.1016/j.celrep.2024.115098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 09/19/2024] [Accepted: 12/02/2024] [Indexed: 12/30/2024] Open
Abstract
The amino acid sequence of the T cell receptor (TCR) varies between T cells of an individual's immune system. Particular TCR residues nearly guarantee mucosal-associated invariant T (MAIT) and natural killer T (NKT) cell transcriptional fates. To define how the TCR sequence affects T cell fates, we analyze the paired αβTCR sequence and transcriptome of 961,531 single cells. We find that hydrophobic complementarity-determining region (CDR)3 residues promote regulatory T cell fates in both the CD8 and CD4 lineages. Most strikingly, we find a set of TCR sequence features that promote the T cell transition from naive to memory. We quantify the extent of these features through our TCR scoring function "TCR-mem." Using TCR transduction experiments, we demonstrate that increased TCR-mem promotes T cell activation, even among T cells that recognize the same antigen. Our results reveal a common set of TCR sequence features that enable T cell activation and immunological memory.
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MESH Headings
- Immunologic Memory/immunology
- Animals
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/chemistry
- Receptors, Antigen, T-Cell/metabolism
- Receptors, Antigen, T-Cell/genetics
- Mice
- Memory T Cells/immunology
- Amino Acid Sequence
- Lymphocyte Activation/immunology
- Complementarity Determining Regions/immunology
- Mice, Inbred C57BL
- Receptors, Antigen, T-Cell, alpha-beta
- CD8-Positive T-Lymphocytes/immunology
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Affiliation(s)
- Kaitlyn A Lagattuta
- Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Ayano C Kohlgruber
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA; Division of Immunology, Boston Children's Hospital, Boston, MA, USA
| | - Nouran S Abdelfattah
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Aparna Nathan
- Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Laurie Rumker
- Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Michael E Birnbaum
- Koch Institute for Integrative Cancer Research, Cambridge, MA, USA; Department of Biomedical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
| | - Stephen J Elledge
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Soumya Raychaudhuri
- Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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Sen Chaudhuri A, Sun J. Lung-resident lymphocytes and their roles in respiratory infections and chronic respiratory diseases. CHINESE MEDICAL JOURNAL PULMONARY AND CRITICAL CARE MEDICINE 2024; 2:214-223. [PMID: 39834580 PMCID: PMC11742555 DOI: 10.1016/j.pccm.2024.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Indexed: 01/22/2025]
Abstract
Recent scientific breakthroughs have blurred traditional boundaries between innate and adaptive immunity, revealing a sophisticated network of tissue-resident cells that deliver immediate, localized immune responses. These lymphocytes not only provide rapid frontline defense but also present a paradoxical role in the pathogenesis of respiratory diseases such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and the long-term tissue consequences of viral infections including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This review traverses the intricate landscape of lung-resident lymphocytes, delving into their origins, diverse functions, and their dualistic impact on pulmonary health. We dissect their interactions with the microenvironment and the regulatory mechanisms guiding their activity, with an emphasis on their contribution to both immune protection and immunopathology. This review aims to elucidate the complex narrative of these cells, enhancing our understanding of the development of precise therapeutic strategies to combat acute and chronic pulmonary diseases. Through this exploration, the review aspires to shed light on the potential of harnessing lung-resident lymphocytes for the treatment of respiratory conditions.
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Affiliation(s)
- Arka Sen Chaudhuri
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA
- Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA
| | - Jie Sun
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA
- Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA
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10
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Loh L, Carcy S, Krovi HS, Domenico J, Spengler A, Lin Y, Torres J, Prabakar RK, Palmer W, Norman PJ, Stone M, Brunetti T, Meyer HV, Gapin L. Unraveling the phenotypic states of human innate-like T cells: Comparative insights with conventional T cells and mouse models. Cell Rep 2024; 43:114705. [PMID: 39264810 PMCID: PMC11552652 DOI: 10.1016/j.celrep.2024.114705] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/23/2024] [Accepted: 08/16/2024] [Indexed: 09/14/2024] Open
Abstract
The "innate-like" T cell compartment, known as Tinn, represents a diverse group of T cells that straddle the boundary between innate and adaptive immunity. We explore the transcriptional landscape of Tinn compared to conventional T cells (Tconv) in the human thymus and blood using single-cell RNA sequencing (scRNA-seq) and flow cytometry. In human blood, the majority of Tinn cells share an effector program driven by specific transcription factors, distinct from those governing Tconv cells. Conversely, only a fraction of thymic Tinn cells displays an effector phenotype, while others share transcriptional features with developing Tconv cells, indicating potential divergent developmental pathways. Unlike the mouse, human Tinn cells do not differentiate into multiple effector subsets but develop a mixed type 1/type 17 effector potential. Cross-species analysis uncovers species-specific distinctions, including the absence of type 2 Tinn cells in humans, which implies distinct immune regulatory mechanisms across species.
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Affiliation(s)
- Liyen Loh
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Salomé Carcy
- School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA; Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
| | | | - Joanne Domenico
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Andrea Spengler
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Yong Lin
- Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
| | - Joshua Torres
- Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
| | - Rishvanth K Prabakar
- Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
| | - William Palmer
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Paul J Norman
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | | | - Tonya Brunetti
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Hannah V Meyer
- Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
| | - Laurent Gapin
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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11
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Zheng Y, Han F, Wu Z, Wang B, Chen X, Boulouis C, Jiang Y, Ho A, He D, Sia WR, Mak JYW, Fairlie DP, Wang LF, Sandberg JK, Lobie PE, Ma S, Leeansyah E. MAIT cell activation and recruitment in inflammation and tissue damage in acute appendicitis. SCIENCE ADVANCES 2024; 10:eadn6331. [PMID: 38865451 PMCID: PMC11168461 DOI: 10.1126/sciadv.adn6331] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 05/08/2024] [Indexed: 06/14/2024]
Abstract
Mucosal-associated invariant T (MAIT) cells are antimicrobial T cells abundant in the gut, but mechanisms for their migration into tissues during inflammation are poorly understood. Here, we used acute pediatric appendicitis (APA), a model of acute intestinal inflammation, to examine these migration mechanisms. MAIT cells were lower in numbers in circulation of patients with APA but were enriched in the inflamed appendix with increased production of proinflammatory cytokines. Using the patient-derived appendix organoid (PDAO) model, we found that circulating MAIT cells treated with inflammatory cytokines elevated in APA up-regulated chemokine receptors, including CCR1, CCR3, and CCR4. They exhibited enhanced infiltration of Escherichia coli-pulsed PDAO in a CCR1-, CCR2-, and CCR4-dependent manner. Close interactions of MAIT cells with infected organoids led to the PDAO structural destruction and death. These findings reveal a previously unidentified mechanism of MAIT cell tissue homing, their participation in tissue damage in APA, and their intricate relationship with mucosal tissues during acute intestinal inflammation in humans.
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Affiliation(s)
- Yichao Zheng
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518055, China
| | - Fei Han
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Zhengyu Wu
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Bingjie Wang
- Department of Pediatric Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou 363000, China
| | - Xingchi Chen
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Caroline Boulouis
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, 14152 Stockholm, Sweden
| | - Yuebin Jiang
- Department of Pathology, Zhangzhou Municipal Hospital of Fujian Province, Zhangzhou 363000, China
| | - Amanda Ho
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518055, China
| | - Dan He
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518055, China
| | - Wan Rong Sia
- Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Jeffrey Y. W. Mak
- Centre for Chemistry and Drug Discovery, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland, Australia
| | - David P. Fairlie
- Centre for Chemistry and Drug Discovery, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland, Australia
| | - Lin-Fa Wang
- Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Johan K. Sandberg
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, 14152 Stockholm, Sweden
| | - Peter E. Lobie
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518055, China
| | - Shaohua Ma
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518055, China
| | - Edwin Leeansyah
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
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12
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Zhang B, Chen P, Zhu J, Lu Y. The quantity, function and anti-tumor effect of Mucosal associated invariant T cells in patients with bladder cancer. Int Immunopharmacol 2024; 133:111892. [PMID: 38663315 DOI: 10.1016/j.intimp.2024.111892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/14/2024] [Accepted: 03/15/2024] [Indexed: 05/12/2024]
Abstract
BACKGROUND Bladder cancer (BC), a prevalent malignancy in the urinary system, often poses challenges for effective treatment. Immunotherapy, harnessing the immune system, has exhibited promise in early-stage clinical trials. Mucosal associated invariant T (MAIT) cells, a subset of immune cells implicated in various diseases, including certain cancer, have yet to be explored in BC patients. We aimed to investigate the quantity, function, and anti-tumor effects of MAIT cells in BC patients. METHODS A total of 75 newly diagnosed BC patients and 183 healthy volunteers were included. Blood samples were collected and analyzed to evaluate the quantity and function of MAIT cells. Surgical resection provided BC tissues for further analysis, and the clinical features of BC tumors were collected and their relationship with MAIT cells was explored. RESULTS MAIT cells were identified in both healthy individuals and BC patients. The proportion of MAIT cells in the peripheral blood of BC patients did not significantly differ from that of healthy controls. However, the study revealed a correlation between the proportion of IFN-γ producing MAIT cells and tumor number and invasion in BC patients. Furthermore, MAIT cells exhibited cytotoxic effects on BC cells in vitro and in vivo. CONCLUSIONS This study sheds light on the role of MAIT cells in BC. While the quantity of MAIT cells showed no significant change in BC patients, their functional attributes and association with tumor characteristics suggest their potential as an immunotherapy target in BC treatment.
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Affiliation(s)
- Baodan Zhang
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Pengcheng Chen
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
| | - Jie Zhu
- Department of Psychiatry, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Yongyong Lu
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
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13
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Huang X, Kantonen J, Nowlan K, Nguyen NA, Jokiranta ST, Kuivanen S, Heikkilä N, Mahzabin S, Kantele A, Vapalahti O, Myllykangas L, Heinonen S, Mäyränpää MI, Strandin T, Kekäläinen E. Mucosal-Associated Invariant T Cells are not susceptible in vitro to SARS-CoV-2 infection but accumulate into the lungs of COVID-19 patients. Virus Res 2024; 341:199315. [PMID: 38211733 PMCID: PMC10826420 DOI: 10.1016/j.virusres.2024.199315] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 12/15/2023] [Accepted: 01/08/2024] [Indexed: 01/13/2024]
Abstract
Prolonged T cell lymphopenia is common in COVID-19, caused by SARS-CoV-2. While the mechanisms of lymphopenia during COVID-19 remain elusive, it is especially pronounced in a specialized innate-like T cell population called Mucosal Associated Invariant T cells (MAITs). MAITs has been suggested to express Angiotensin-Converting Enzyme 2 (ACE2), which is the well-known cellular receptor for SARS-CoV-2. However, it is still unclear if SARS-CoV-2 can infect or affect MAIT cells directly. In this study, we performed multicolor flow cytometry on peripheral blood mononuclear cells obtained from COVID-19 patients to assess the frequencies of CD8+Vα7.2+CD161+ MAIT subsets at acute and convalescent disease phases. The susceptibility of MAITs and T cells to direct exposure by SARS-CoV-2 was analysed using cells isolated from healthy donor buffy coats by viability assays, virus-specific RT-PCR, and flow cytometry. In situ lung immunofluorescence was used to evaluate retention of T cells, especially MAIT cells, in lung tissues during acute COVID-19. Our study confirms previous reports indicating that circulating MAITs are activated, and their frequency is declined in patients with acute SARS-CoV-2 infection, whereas an accumulation of MAITs and T cells was seen in the lung tissue of individuals with fatal COVID-19. However, despite a fraction of MAITs found to express ACE2, no evidence for the susceptibility of MAITs for direct infection or activation by SARS-CoV-2 particles was observed. Thus, their activation and decline in the circulation is most likely explained by indirect mechanisms involving other immune cells and cytokine-induced pro-inflammatory environment but not by direct exposure to viral particles at the infection site.
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Affiliation(s)
- Xiaobo Huang
- Translational Immunology Research Program, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland.
| | - Jonas Kantonen
- Department of Pathology, University of Helsinki, Helsinki, Finland; Department of Pathology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
| | - Kirsten Nowlan
- Translational Immunology Research Program, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
| | - Ngoc Anh Nguyen
- Translational Immunology Research Program, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
| | - Suvi T Jokiranta
- Translational Immunology Research Program, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
| | - Suvi Kuivanen
- Department of Virology, Medicum, University of Helsinki, Helsinki, Finland; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, Berlin, Germany
| | - Nelli Heikkilä
- Translational Immunology Research Program, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Center of Vaccinology, University of Geneva, Geneva, Switzerland
| | - Shamita Mahzabin
- Translational Immunology Research Program, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Anu Kantele
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Meilahti Vaccine Research Center, MeVac, Infectious Diseases, Helsinki University and Helsinki University Hospital, Helsinki, Finland
| | - Olli Vapalahti
- Division of Virology and Immunology, HUS Diagnostic Center, HUSLAB Clinical Microbiology, Helsinki, Finland; Zoonosis Unit, Department of Virology, Medicum, University of Helsinki, Helsinki, Finland; Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland
| | - Liisa Myllykangas
- Department of Pathology, University of Helsinki, Helsinki, Finland; Department of Pathology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
| | - Santtu Heinonen
- New Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Mikko I Mäyränpää
- Department of Pathology, University of Helsinki, Helsinki, Finland; Department of Pathology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
| | - Tomas Strandin
- Zoonosis Unit, Department of Virology, Medicum, University of Helsinki, Helsinki, Finland
| | - Eliisa Kekäläinen
- Translational Immunology Research Program, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland; Division of Virology and Immunology, HUS Diagnostic Center, HUSLAB Clinical Microbiology, Helsinki, Finland
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14
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Liu J, Joseph S, Manohar K, Lee J, Brokaw JP, Shelley WC, Markel TA. Role of innate T cells in necrotizing enterocolitis. Front Immunol 2024; 15:1357483. [PMID: 38390341 PMCID: PMC10881895 DOI: 10.3389/fimmu.2024.1357483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 01/16/2024] [Indexed: 02/24/2024] Open
Abstract
Necrotizing enterocolitis (NEC) is a destructive gastrointestinal disease primarily affecting preterm babies. Despite advancements in neonatal care, NEC remains a significant cause of morbidity and mortality in neonatal intensive care units worldwide and the etiology of NEC is still unclear. Risk factors for NEC include prematurity, very low birth weight, feeding with formula, intestinal dysbiosis and bacterial infection. A review of the literature would suggest that supplementation of prebiotics and probiotics prevents NEC by altering the immune responses. Innate T cells, a highly conserved subpopulation of T cells that responds quickly to stimulation, develops differently from conventional T cells in neonates. This review aims to provide a succinct overview of innate T cells in neonates, encompassing their phenotypic characteristics, functional roles, likely involvement in the pathogenesis of NEC, and potential therapeutic implications.
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Affiliation(s)
- Jianyun Liu
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Sharon Joseph
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Krishna Manohar
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Jasmine Lee
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - John P. Brokaw
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - W. Christopher Shelley
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
- Riley Hospital for Children at Indiana University Health, Indianapolis, IN, United States
| | - Troy A. Markel
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
- Riley Hospital for Children at Indiana University Health, Indianapolis, IN, United States
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15
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Wang P, Fredj Z, Zhang H, Rong G, Bian S, Sawan M. Blocking Superantigen-Mediated Diseases: Challenges and Future Trends. J Immunol Res 2024; 2024:2313062. [PMID: 38268531 PMCID: PMC10807946 DOI: 10.1155/2024/2313062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/15/2023] [Accepted: 12/30/2023] [Indexed: 01/26/2024] Open
Abstract
Superantigens are virulence factors secreted by microorganisms that can cause various immune diseases, such as overactivating the immune system, resulting in cytokine storms, rheumatoid arthritis, and multiple sclerosis. Some studies have demonstrated that superantigens do not require intracellular processing and instated bind as intact proteins to the antigen-binding groove of major histocompatibility complex II on antigen-presenting cells, resulting in the activation of T cells with different T-cell receptor Vβ and subsequent overstimulation. To combat superantigen-mediated diseases, researchers have employed different approaches, such as antibodies and simulated peptides. However, due to the complex nature of superantigens, these approaches have not been entirely successful in achieving optimal therapeutic outcomes. CD28 interacts with members of the B7 molecule family to activate T cells. Its mimicking peptide has been suggested as a potential candidate to block superantigens, but it can lead to reduced T-cell activity while increasing the host's infection risk. Thus, this review focuses on the use of drug delivery methods to accurately target and block superantigens, while reducing the adverse effects associated with CD28 mimic peptides. We believe that this method has the potential to provide an effective and safe therapeutic strategy for superantigen-mediated diseases.
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Affiliation(s)
- Pengbo Wang
- CenBRAIN Neurotech, School of Engineering, Westlake University, Hangzhou 310030, China
| | - Zina Fredj
- CenBRAIN Neurotech, School of Engineering, Westlake University, Hangzhou 310030, China
| | - Hongyong Zhang
- CenBRAIN Neurotech, School of Engineering, Westlake University, Hangzhou 310030, China
| | - Guoguang Rong
- CenBRAIN Neurotech, School of Engineering, Westlake University, Hangzhou 310030, China
| | - Sumin Bian
- CenBRAIN Neurotech, School of Engineering, Westlake University, Hangzhou 310030, China
| | - Mohamad Sawan
- CenBRAIN Neurotech, School of Engineering, Westlake University, Hangzhou 310030, China
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16
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Li Y, Li C, Wang Q, Ye YJ, Jiang KW. Transcriptomic and genomic profiling of multiple primary colorectal cancers reveals intratumor heterogeneity and a distinct immune microenvironment. Int Immunopharmacol 2024; 126:111276. [PMID: 38016348 DOI: 10.1016/j.intimp.2023.111276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 11/14/2023] [Accepted: 11/20/2023] [Indexed: 11/30/2023]
Abstract
This study reported on the intratumor genomic and immunological heterogeneity of different tumor lesions from a single patient with multiple primary colorectal cancer (MPCC). The goal of this study was to explore the molecular and microenvironment characteristics of tumor lesions from different primary sites in a patient with MPCC. A total of three tumor lesions located in the hepatic flexure of the transverse colon, sigmoid colon, and rectum were collected from a 72-year-old male patient with MPCC. All three tumor samples were examined by using whole-exome sequencing (WES) and single-cell RNA sequencing (scRNA-seq). The transcriptome data of The Cancer Genome Atlas (TCGA) colon cancer (COAD) dataset were explored to characterize the biological impacts of certain immune cells. Only three nonsynonymous mutations were shared by all of the tumor lesions, whereas a number of single nucleotide variant (SNV) and copy number variation (CNV) mutations were shared by tumor samples from the sigmoid colon and rectum. Transcriptomic analysis showed that tumor lesions derived from the transverse colon had decreased levels of RTK, ERK, and AKT pathway activity, thus suggesting lower oncogenic properties in the transverse lesion compared to the other two samples. Further immune landscape evaluation by using single-cell transcriptomic analysis displayed significant intratumor heterogeneity in MPCC. Specifically, more abundant mucosal-associated invariant T (MAIT) cell infiltration was found in transverse colon tumor lesions. Afterwards, we found that higher MAIT cell infiltration may correlate with a better prognosis of patients with colon cancer (immunohistochemical status was MSI-L/pMMR) by using a publicly available TCGA dataset.
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Affiliation(s)
- Yang Li
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing 100050, China; Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing 100044, China
| | - Chen Li
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing 100044, China
| | - Quan Wang
- Ambulatory Surgery Center, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, China
| | - Ying-Jiang Ye
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing 100044, China
| | - Ke-Wei Jiang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing 100044, China.
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17
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Shimizu Y, Sugimoto C, Wakao H. Potential of MAIT cells to modulate asthma. Allergol Int 2024; 73:40-47. [PMID: 37567833 DOI: 10.1016/j.alit.2023.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/10/2023] [Accepted: 07/19/2023] [Indexed: 08/13/2023] Open
Abstract
Despite recent advances in asthma treatments, the search for novel therapies remains necessary because there are still patients with recurrent asthma exacerbations and poor responses to the existing treatments. Since group 2 innate lymphoid cells (ILC2) play a pivotal role in asthma by triggering and exacerbating type 2 inflammation, controlling ILC2s function is key to combating severe asthma. Mucosal-associated invariant T (MAIT) cells are innate-like T cells abundant in humans and are activated both in a T cell receptor-dependent and -independent manner. MAIT cells are composed of MAIT1 and MAIT17 based on the expression of transcription factors T-bet and RORγt, respectively. MAIT cells play pivotal roles in host defense against pathogens and in tissue repair and are essential for the maintenance of immunity and hemostasis. Our recent studies revealed that MAIT cells inhibit both ILC2 proliferation and functions in a mouse model of airway inflammation. MAIT cells may alleviate airway inflammation in two ways, by promoting airway epithelial cell barrier repair and by repressing ILC2s. Therefore, reagents that promote MAIT cell-mediated suppression of ILC2 proliferation and function, or designer MAIT cells (genetically engineered to suppress ILC2s or promote repair of airway damage), may be effective therapeutic agents for severe asthma.
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Affiliation(s)
- Yasuo Shimizu
- Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Tochigi, Japan; Respiratory Endoscopy Center, Dokkyo Medical University Hospital, Tochigi, Japan; Regenerative Center, Dokkyo Medical University Hospital, Tochigi, Japan.
| | - Chie Sugimoto
- Center for the Frontier Medicine, Host Defense Division, Dokkyo Medical University, Tochigi, Japan
| | - Hiroshi Wakao
- Center for the Frontier Medicine, Host Defense Division, Dokkyo Medical University, Tochigi, Japan
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18
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Wu S, Yang X, Lou Y, Xiao X. MAIT cells in bacterial infectious diseases: heroes, villains, or both? Clin Exp Immunol 2023; 214:144-153. [PMID: 37624404 PMCID: PMC10714195 DOI: 10.1093/cei/uxad102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 08/20/2023] [Accepted: 08/21/2023] [Indexed: 08/26/2023] Open
Abstract
Due to the aggravation of bacterial drug resistance and the lag in the development of new antibiotics, it is crucial to develop novel therapeutic regimens for bacterial infectious diseases. Currently, immunotherapy is a promising regimen for the treatment of infectious diseases. Mucosal-associated invariant T (MAIT) cells, a subpopulation of innate-like T cells, are abundant in humans and can mount a rapid immune response to pathogens, thus becoming a potential target of immunotherapy for infectious diseases. At the site of infection, activated MAIT cells perform complex biological functions by secreting a variety of cytokines and cytotoxic substances. Many studies have shown that MAIT cells have immunoprotective effects because they can bridge innate and adaptive immune responses, leading to bacterial clearance, tissue repair, and homeostasis maintenance. MAIT cells also participate in cytokine storm generation, tissue fibrosis, and cancer progression, indicating that they play a role in immunopathology. In this article, we review recent studies of MAIT cells, discuss their dual roles in bacterial infectious diseases and provide some promising MAIT cell-targeting strategies for the treatment of bacterial infectious diseases.
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Affiliation(s)
- Sihong Wu
- Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xi Yang
- Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yongliang Lou
- Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xingxing Xiao
- Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
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19
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Chengalroyen MD. Current Perspectives and Challenges of MAIT Cell-Directed Therapy for Tuberculosis Infection. Pathogens 2023; 12:1343. [PMID: 38003807 PMCID: PMC10675005 DOI: 10.3390/pathogens12111343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 10/27/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
Mucosal-associated invariant T (MAIT) cells are a distinct population of non-conventional T cells that have been preserved through evolution and possess properties of both innate and adaptive immune cells. They are activated through the recognition of antigens presented by non-polymorphic MR1 proteins or, alternately, can be stimulated by specific cytokines. These cells are multifaceted and exert robust antimicrobial activity against bacterial and viral infections, direct the immune response through the modulation of other immune cells, and exhibit a specialized tissue homeostasis and repair function. These distinct characteristics have instigated interest in MAIT cell biology for immunotherapy and vaccine development. This review describes the current understanding of MAIT cell activation, their role in infections and diseases with an emphasis on tuberculosis (TB) infection, and perspectives on the future use of MAIT cells in immune-mediated therapy.
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Affiliation(s)
- Melissa D Chengalroyen
- Molecular Mycobacteriology Research Unit, Institute of Infectious Disease and Molecular Medicine, Department of Pathology, University of Cape Town, Cape Town 7700, South Africa
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20
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Konecny AJ, Shows DM, Lord JD. Colonic mucosal associated invariant T cells in Crohn's disease have a diverse and non-public T cell receptor beta chain repertoire. PLoS One 2023; 18:e0285918. [PMID: 37922286 PMCID: PMC10624325 DOI: 10.1371/journal.pone.0285918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 10/13/2023] [Indexed: 11/05/2023] Open
Abstract
OBJECTIVES Mucosal-Associated Invariant T (MAIT) cells are T cells with a semi-invariant T cell receptor (TCR), recognizing riboflavin precursors presented by a non-polymorphic MR1 molecule. As these precursors are produced by the gut microbiome, we characterized the frequency, phenotype and clonality of MAIT cells in human colons with and without Crohn's disease (CD). METHODS The transcriptome of MAIT cells sorted from blood and intestinal lamina propria cells from colectomy recipients were compared with other CD8+ T cells. Colon biopsies from an additional ten CD patients and ten healthy controls (HC) were analyzed by flow cytometry. TCR genes were sequenced from individual MAIT cells from these biopsies and compared with those of MAIT cells from autologous blood. RESULTS MAIT cells in the blood and colon showed a transcriptome distinct from other CD8 T cells, with more expression of the IL-23 receptor. MAIT cells were enriched in the colons of CD patients, with less NKG2D in inflamed versus uninflamed segments. Regardless of disease, most MAIT cells expressed integrin α4β7 in the colon but not in the blood, where they were enriched for α4β7 expression. TCR sequencing revealed heterogeneity in the colon and blood, with few public sequences associated with cohorts. CONCLUSION MAIT cells are enriched in the colons of CD patients and disproportionately express molecules (IL-23R, integrin α4β7) targeted by CD therapeutics, to suggest a pathogenic role for them in CD. Public TCR sequences were neither common nor sufficiently restricted to a cohort to suggest protective or pathogenic antigen-specificities.
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Affiliation(s)
- Andrew J. Konecny
- Benaroya Research Institute, Translational Research Program, Seattle, WA, United States of America
- Department of Immunology, University of Washington, Seattle, WA, United States of America
| | - Donna M. Shows
- Benaroya Research Institute, Translational Research Program, Seattle, WA, United States of America
| | - James D. Lord
- Benaroya Research Institute, Translational Research Program, Seattle, WA, United States of America
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21
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Zheng Y, Han F, Ho A, Xue Y, Wu Z, Chen X, Sandberg JK, Ma S, Leeansyah E. Role of MAIT cells in gastrointestinal tract bacterial infections in humans: More than a gut feeling. Mucosal Immunol 2023; 16:740-752. [PMID: 37353006 DOI: 10.1016/j.mucimm.2023.06.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/12/2023] [Accepted: 06/15/2023] [Indexed: 06/25/2023]
Abstract
Mucosa-associated invariant T (MAIT) cells are the largest population of unconventional T cells in humans. These antimicrobial T cells are poised with rapid effector responses following recognition of the cognate riboflavin (vitamin B2)-like metabolite antigens derived from microbial riboflavin biosynthetic pathway. Presentation of this unique class of small molecule metabolite antigens is mediated by the highly evolutionarily conserved major histocompatibility complex class I-related protein. In humans, MAIT cells are widely found along the upper and lower gastrointestinal tracts owing to their high expression of chemokine receptors and homing molecules directing them to these tissue sites. In this review, we discuss recent findings regarding the roles MAIT cells play in various gastrointestinal bacterial infections, and how their roles appear to differ depending on the etiological agents and the anatomical location. We further discuss the potential mechanisms by which MAIT cells contribute to pathogen control, orchestrate adaptive immunity, as well as their potential contribution to inflammation and tissue damage during gastrointestinal bacterial infections, and the ensuing tissue repair following resolution. Finally, we propose and discuss the use of the emerging three-dimensional organoid technology to test different hypotheses regarding the role of MAIT cells in gastrointestinal bacterial infections, inflammation, and immunity.
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Affiliation(s)
- Yichao Zheng
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China; Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, China
| | - Fei Han
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
| | - Amanda Ho
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China; Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, China
| | - Yiting Xue
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China; Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, China
| | - Zhengyu Wu
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
| | - Xingchi Chen
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
| | - Johan K Sandberg
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Shaohua Ma
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China; Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, China
| | - Edwin Leeansyah
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China.
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22
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Kurioka A, Klenerman P. Aging unconventionally: γδ T cells, iNKT cells, and MAIT cells in aging. Semin Immunol 2023; 69:101816. [PMID: 37536148 PMCID: PMC10804939 DOI: 10.1016/j.smim.2023.101816] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 07/19/2023] [Accepted: 07/20/2023] [Indexed: 08/05/2023]
Abstract
Unconventional T cells include γδ T cells, invariant Natural Killer T cells (iNKT) cells and Mucosal Associated Invariant T (MAIT) cells, which are distinguished from conventional T cells by their recognition of non-peptide ligands presented by non-polymorphic antigen presenting molecules and rapid effector functions that are pre-programmed during their development. Here we review current knowledge of the effect of age on unconventional T cells, from early life to old age, in both mice and humans. We then discuss the role of unconventional T cells in age-associated diseases and infections, highlighting the similarities between members of the unconventional T cell family in the context of aging.
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Affiliation(s)
- Ayako Kurioka
- Nuffield Department of Medicine, University of Oxford, Oxford, UK.
| | - Paul Klenerman
- Nuffield Department of Medicine, University of Oxford, Oxford, UK; Translational Gastroenterology Unit, University of Oxford, Oxford, UK
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23
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Lagattuta KA, Nathan A, Rumker L, Birnbaum ME, Raychaudhuri S. The T cell receptor sequence influences the likelihood of T cell memory formation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.20.549939. [PMID: 37502994 PMCID: PMC10370203 DOI: 10.1101/2023.07.20.549939] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
T cell differentiation depends on activation through the T cell receptor (TCR), whose amino acid sequence varies cell to cell. Particular TCR amino acid sequences nearly guarantee Mucosal-Associated Invariant T (MAIT) and Natural Killer T (NKT) cell fates. To comprehensively define how TCR amino acids affects all T cell fates, we analyze the paired αβTCR sequence and transcriptome of 819,772 single cells. We find that hydrophobic CDR3 residues promote regulatory T cell transcriptional states in both the CD8 and CD4 lineages. Most strikingly, we find a set of TCR sequence features, concentrated in CDR2α, that promotes positive selection in the thymus as well as transition from naïve to memory in the periphery. Even among T cells that recognize the same antigen, these TCR sequence features help to explain which T cells form immunological memory, which is essential for effective pathogen response.
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Affiliation(s)
- Kaitlyn A. Lagattuta
- Center for Data Sciences, Brigham and Women’s Hospital, Boston, MA, USA
- Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Aparna Nathan
- Center for Data Sciences, Brigham and Women’s Hospital, Boston, MA, USA
- Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Laurie Rumker
- Center for Data Sciences, Brigham and Women’s Hospital, Boston, MA, USA
- Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Michael E. Birnbaum
- Koch Institute for Integrative Cancer Research, Cambridge, MA, USA
- Department of Biomedical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
| | - Soumya Raychaudhuri
- Center for Data Sciences, Brigham and Women’s Hospital, Boston, MA, USA
- Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
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24
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Wang NI, Ninkov M, Haeryfar SMM. Classic costimulatory interactions in MAIT cell responses: from gene expression to immune regulation. Clin Exp Immunol 2023; 213:50-66. [PMID: 37279566 PMCID: PMC10324557 DOI: 10.1093/cei/uxad061] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 05/17/2023] [Accepted: 06/01/2023] [Indexed: 06/08/2023] Open
Abstract
Mucosa-associated invariant T (MAIT) cells are evolutionarily conserved, innate-like T lymphocytes with enormous immunomodulatory potentials. Due to their strategic localization, their invariant T cell receptor (iTCR) specificity for major histocompatibility complex-related protein 1 (MR1) ligands of commensal and pathogenic bacterial origin, and their sensitivity to infection-elicited cytokines, MAIT cells are best known for their antimicrobial characteristics. However, they are thought to also play important parts in the contexts of cancer, autoimmunity, vaccine-induced immunity, and tissue repair. While cognate MR1 ligands and cytokine cues govern MAIT cell maturation, polarization, and peripheral activation, other signal transduction pathways, including those mediated by costimulatory interactions, regulate MAIT cell responses. Activated MAIT cells exhibit cytolytic activities and secrete potent inflammatory cytokines of their own, thus transregulating the biological behaviors of several other cell types, including dendritic cells, macrophages, natural killer cells, conventional T cells, and B cells, with significant implications in health and disease. Therefore, an in-depth understanding of how costimulatory pathways control MAIT cell responses may introduce new targets for optimized MR1/MAIT cell-based interventions. Herein, we compare and contrast MAIT cells and mainstream T cells for their expression of classic costimulatory molecules belonging to the immunoglobulin superfamily and the tumor necrosis factor (TNF)/TNF receptor superfamily, based not only on the available literature but also on our transcriptomic analyses. We discuss how these molecules participate in MAIT cells' development and activities. Finally, we introduce several pressing questions vis-à-vis MAIT cell costimulation and offer new directions for future research in this area.
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Affiliation(s)
- Nicole I Wang
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - Marina Ninkov
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - S M Mansour Haeryfar
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
- Division of Clinical Immunology and Allergy, Department of Medicine, Western University, London, Ontario, Canada
- Division of General Surgery, Department of Surgery, Western University, London, Ontario, Canada
- Lawson Health Research Institute, London, Ontario, Canada
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25
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Dou Y, Shan S, Zhang J. UcTCRdb: An unconventional T cell receptor sequence database with online analysis functions. Front Immunol 2023; 14:1158295. [PMID: 36993970 PMCID: PMC10040587 DOI: 10.3389/fimmu.2023.1158295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 03/02/2023] [Indexed: 03/14/2023] Open
Abstract
Unlike conventional major histocompatibility complex (MHC) class I and II molecules reactive T cells, the unconventional T cell subpopulations recognize various non-polymorphic antigen-presenting molecules and are typically characterized by simplified patterns of T cell receptors (TCRs), rapid effector responses and ‘public’ antigen specificities. Dissecting the recognition patterns of the non-MHC antigens by unconventional TCRs can help us further our understanding of the unconventional T cell immunity. The small size and irregularities of the released unconventional TCR sequences are far from high-quality to support systemic analysis of unconventional TCR repertoire. Here we present UcTCRdb, a database that contains 669,900 unconventional TCRs collected from 34 corresponding studies in humans, mice, and cattle. In UcTCRdb, users can interactively browse TCR features of different unconventional T cell subsets in different species, search and download sequences under different conditions. Additionally, basic and advanced online TCR analysis tools have been integrated into the database, which will facilitate the study of unconventional TCR patterns for users with different backgrounds. UcTCRdb is freely available at http://uctcrdb.cn/.
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26
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Jiang X, Zhao Q, Huang Z, Ma F, Chen K, Li Z. Relevant mechanisms of MAIT cells involved in the pathogenesis of periodontitis. Front Cell Infect Microbiol 2023; 13:1104932. [PMID: 36896188 PMCID: PMC9988952 DOI: 10.3389/fcimb.2023.1104932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 01/31/2023] [Indexed: 02/23/2023] Open
Abstract
Mucosal-associated invariant T (MAIT) cells are a group of unconventional T cells that are abundant in the human body, recognize microbial-derived vitamin B metabolites presented by MHC class I-related protein 1 (MR1), and rapidly produce proinflammatory cytokines, which are widely involved in the immune response to various infectious diseases. In the oral mucosa, MAIT cells tend to accumulate near the mucosal basal lamina and are more inclined to secrete IL-17 when activated. Periodontitis is a group of diseases that manifests mainly as inflammation of the gums and resorption of the alveolar bone due to periodontal tissue invasion by plaque bacteria on the dental surface. The course of periodontitis is often accompanied by a T-cell-mediated immune response. This paper discussed the pathogenesis of periodontitis and the potential contribution of MAIT cells to periodontitis.
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Affiliation(s)
- Xinrong Jiang
- Hospital of Stomatology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangzhou, Guangdong, China
- College of Stomatology, Jinan University, Guangzhou, Guangdong, China
| | - Qingtong Zhao
- Hospital of Stomatology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangzhou, Guangdong, China
- Department of Stomatology, The Sixth Affiliated Hospital of Jinan University, Dongguan, Guangdong, China
| | - Zhanyu Huang
- Hospital of Stomatology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangzhou, Guangdong, China
- College of Stomatology, Jinan University, Guangzhou, Guangdong, China
| | - Fengyu Ma
- Hospital of Stomatology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangzhou, Guangdong, China
- College of Stomatology, Jinan University, Guangzhou, Guangdong, China
| | - Kexiao Chen
- Hospital of Stomatology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangzhou, Guangdong, China
- College of Stomatology, Jinan University, Guangzhou, Guangdong, China
| | - Zejian Li
- Hospital of Stomatology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangzhou, Guangdong, China
- Chaoshan Hospital, The First Affiliated Hospital of Jinan University, Chaozhou, Guangdong, China
- *Correspondence: Zejian Li,
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27
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Zhang H, Shen H, Zhou L, Xie L, Kong D, Wang H. Mucosal-Associated Invariant T Cells in the Digestive System: Defender or Destroyer? Cell Mol Gastroenterol Hepatol 2023; 15:809-819. [PMID: 36584816 PMCID: PMC9971522 DOI: 10.1016/j.jcmgh.2022.12.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 12/22/2022] [Accepted: 12/22/2022] [Indexed: 01/01/2023]
Abstract
Mucosal-associated invariant T (MAIT) cells are a subset of innate T lymphocytes that express the semi-invariant T cell receptor and recognize riboflavin metabolites via the major histocompatibility complex class I-related protein. Given the abundance of MAIT cells in the human body, their role in human diseases has been increasingly studied in recent years. MAIT cells may serve as targets for clinical therapy. Specifically, this review discusses how MAIT cells are altered in gastric, esophageal, intestinal, and hepatobiliary diseases and describes their protective or pathogenic roles. A greater understanding of MAIT cells will provide a more favorable therapeutic approach for digestive diseases in the clinical field.
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Affiliation(s)
- Hejiao Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Haiyuan Shen
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Liangliang Zhou
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Linxi Xie
- School of Basic Medical Science, Anhui Medical University, Hefei, China
| | - Derun Kong
- Department of Gastroenterology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China.
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28
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LeBlanc G, Kreissl F, Melamed J, Sobel AL, Constantinides MG. The role of unconventional T cells in maintaining tissue homeostasis. Semin Immunol 2022; 61-64:101656. [PMID: 36306662 PMCID: PMC9828956 DOI: 10.1016/j.smim.2022.101656] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 09/01/2022] [Accepted: 09/21/2022] [Indexed: 01/12/2023]
Affiliation(s)
- Gabrielle LeBlanc
- Department of Immunology & Microbiology, Scripps Research, La Jolla, CA 92037, USA,These authors contributed equally
| | - Felix Kreissl
- Department of Immunology & Microbiology, Scripps Research, La Jolla, CA 92037, USA,These authors contributed equally
| | - Jonathan Melamed
- Department of Immunology & Microbiology, Scripps Research, La Jolla, CA 92037, USA,These authors contributed equally
| | - Adam L. Sobel
- Department of Immunology & Microbiology, Scripps Research, La Jolla, CA 92037, USA,These authors contributed equally
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29
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Darrigues J, Almeida V, Conti E, Ribot JC. The multisensory regulation of unconventional T cell homeostasis. Semin Immunol 2022; 61-64:101657. [PMID: 36370671 DOI: 10.1016/j.smim.2022.101657] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/29/2022] [Accepted: 09/21/2022] [Indexed: 12/14/2022]
Abstract
Unconventional T cells typically group γδ T cells, invariant Natural Killer T cells (NKT) and Mucosal Associated Invariant T (MAIT) cells. With their pre-activated status and biased tropism for non-lymphoid organs, they provide a rapid (innate-like) and efficient first line of defense against pathogens at strategical barrier sites, while they can also trigger chronic inflammation, and unexpectedly contribute to steady state physiology. Thus, a tight control of their homeostasis is critical to maintain tissue integrity. In this review, we discuss the recent advances of our understanding of the factors, from neuroimmune to inflammatory regulators, shaping the size and functional properties of unconventional T cell subsets in non-lymphoid organs. We present a general overview of the mechanisms common to these populations, while also acknowledging specific aspects of their diversity. We mainly focus on their maintenance at steady state and upon inflammation, highlighting some key unresolved issues and raising upcoming technical, fundamental and translational challenges.
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Affiliation(s)
- Julie Darrigues
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal.
| | - Vicente Almeida
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal
| | - Eller Conti
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal
| | - Julie C Ribot
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal.
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30
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Han F, Gulam MY, Zheng Y, Zulhaimi NS, Sia WR, He D, Ho A, Hadadi L, Liu Z, Qin P, Lobie PE, Kamarulzaman A, Wang LF, Sandberg JK, Lewin SR, Rajasuriar R, Leeansyah E. IL7RA single nucleotide polymorphisms are associated with the size and function of the MAIT cell population in treated HIV-1 infection. Front Immunol 2022; 13:985385. [PMID: 36341446 PMCID: PMC9632172 DOI: 10.3389/fimmu.2022.985385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 10/04/2022] [Indexed: 11/24/2022] Open
Abstract
MAIT cells are persistently depleted and functionally exhausted in HIV-1-infected patients despite long-term combination antiretroviral therapy (cART). IL-7 treatment supports MAIT cell reconstitution in vivo HIV-1-infected individuals and rescues their functionality in vitro. Single-nucleotide polymorphisms (SNPs) of the IL-7RA gene modulate the levels of soluble(s)IL-7Rα (sCD127) levels and influence bioavailability of circulating IL-7. Here we evaluate the potential influence of IL-7RA polymorphisms on MAIT cell numbers and function in healthy control (HC) subjects and HIV-1-infected individuals on long-term cART. Our findings indicate that IL-7RA haplotype 2 (H2*T), defined as T-allele carriers at the tagging SNP rs6897932, affects the size of the peripheral blood MAIT cell pool, as well as their production of cytokines and cytolytic effector proteins in response to bacterial stimulation. H2*T carriers had lower sIL-7Rα levels and higher MAIT cell frequency with enhanced functionality linked to higher expression of MAIT cell-associated transcription factors. Despite an average of 7 years on suppressive cART, MAIT cell levels and function in HIV-1-infected individuals were still significantly lower than those of HC. Notably, we observed a significant correlation between MAIT cell levels and cART duration only in HIV-1-infected individuals carrying IL-7RA haplotype 2. Interestingly, treatment with sIL-7Rα in vitro suppressed IL-7-dependent MAIT cell proliferation and function following cognate stimulations. These observations suggest that sIL-7Rα levels may influence MAIT cell numbers and function in vivo by limiting IL-7 bioavailability to MAIT cells. Collectively, these observations suggest that IL-7RA polymorphisms may play a significant role in MAIT cell biology and influence MAIT cells recovery in HIV-1 infection. The potential links between IL7RA polymorphisms, MAIT cell immunobiology, and HIV-1 infection warrant further studies going forward.
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Affiliation(s)
- Fei Han
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
- Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, China
| | - Muhammad Yaaseen Gulam
- Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Yichao Zheng
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
- Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, China
| | - Nurul Syuhada Zulhaimi
- Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia
- Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Wan Rong Sia
- Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Dan He
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
- Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, China
| | - Amanda Ho
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
- Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, China
| | - Leila Hadadi
- Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Zhenyu Liu
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
- Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, China
| | - Peiwu Qin
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
- Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, China
| | - Peter E. Lobie
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
- Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, China
| | - Adeeba Kamarulzaman
- Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia
- Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Lin-Fa Wang
- Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Johan K. Sandberg
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Sharon R. Lewin
- Peter Doherty Institute for Infection and Immunity, Melbourne University, Victoria, Australia
| | - Reena Rajasuriar
- Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia
- Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
- Peter Doherty Institute for Infection and Immunity, Melbourne University, Victoria, Australia
| | - Edwin Leeansyah
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
- Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, China
- Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- *Correspondence: Edwin Leeansyah,
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31
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Tian J, Yan C, Jiang Y, Zhou H, Li L, Shen J, Wang J, Sun H, Yang G, Sun W. Peripheral and intestinal mucosal-associated invariant T cells in premature infants with necrotizing enterocolitis. Front Pharmacol 2022; 13:1008080. [PMID: 36188574 PMCID: PMC9515899 DOI: 10.3389/fphar.2022.1008080] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 08/18/2022] [Indexed: 12/04/2022] Open
Abstract
Background: Necrotizing enterocolitis (NEC) is a potentially fatal inflammatory gastrointestinal disease in preterm infants with unknown pathogenesis. Mucosal-associated invariant T (MAIT) cells primarily accumulate at sites where exposure to microbes is ubiquitous and regulate immunological responses. As the implications of these cells in NEC development in premature infants remain unknown, we investigated the role and characteristics of MAIT cells in NEC pathogenesis. Methods: The percentage of different MAIT cell subsets in peripheral blood samples of 30 preterm infants with NEC and 22 control subjects was estimated using flow cytometry. The frequency of MAIT cells in the intestinal tissues of five NEC patients and five control subjects was also examined. The level of serum cytokines was estimated using cytometric bead array. Potential associations between the different measurements were analyzed using the Spearman’s correlation test. Results: Compared with controls, the NEC patients were found to have significantly reduced percentages of circulating CD161+ CD3+ CD8αα+ T cells and CD161+ CD3+ TCRγδ-TCRVa7.2+ MAIT cells. In the intestinal tissues, the percentage of MAIT cells was significantly higher in samples from the NEC patients than the controls. Furthermore, the percentage of circulating MAIT cells in the peripheral blood samples was inversely correlated with that in the intestinal tissues of the NEC patients. The percentage of CD8αα+ MAIT cells was found to be significantly reduced in both peripheral blood and intestinal tissues of NEC patients. Following treatment, the frequency of circulating MAIT cells significantly increased in NEC patients and reached a level similar to that in the control subjects. However, there was no difference in the percentage of circulating CD8αα+ MAIT cells before and after treatment in the NEC patients. Conclusion: Our results suggested that during the development of NEC MAIT cells accumulate in the inflammatory intestinal tissues, while the percentage of CD8aa+ MAIT cells is significantly decreased, which may lead to the dysfunction of MAIT cells in gut immunity.
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Affiliation(s)
- Jiayi Tian
- Center for Reproductive Medicine and Center for Prenatal Diagnosis, First Hospital, Jilin University, Changchun, China
| | - Chaoying Yan
- Department of Neonatology, The First Hospital of Jilin University, Changchun, China
| | - Yanfang Jiang
- Department of Center of Gene Diagnosis, The First Hospital of Jilin University, Changchun, China
| | - Haohan Zhou
- Department of Orthopaedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Liyuan Li
- Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Jingjing Shen
- School of Civil Engineering and Architecture, Taizhou University, Taizhou, China
| | - Jian Wang
- Department of Neonatology, The First Hospital of Jilin University, Changchun, China
| | - Hongyu Sun
- Department of Orthopaedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Guang Yang
- Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Wei Sun
- Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, China
- *Correspondence: Wei Sun,
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Meermeier EW, Zheng CL, Tran JG, Soma S, Worley AH, Weiss DI, Modlin RL, Swarbrick G, Karamooz E, Khuzwayo S, Wong EB, Gold MC, Lewinsohn DM. Human lung-resident mucosal-associated invariant T cells are abundant, express antimicrobial proteins, and are cytokine responsive. Commun Biol 2022; 5:942. [PMID: 36085311 PMCID: PMC9463188 DOI: 10.1038/s42003-022-03823-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 08/09/2022] [Indexed: 12/02/2022] Open
Abstract
Mucosal-associated Invariant T (MAIT) cells are an innate-like T cell subset that recognize a broad array of microbial pathogens, including respiratory pathogens. Here we investigate the transcriptional profile of MAIT cells localized to the human lung, and postulate that MAIT cells may play a role in maintaining homeostasis at this mucosal barrier. Using the MR1/5-OP-RU tetramer, we identified MAIT cells and non-MAIT CD8+ T cells in lung tissue not suitable for transplant from human donors. We used RNA-sequencing of MAIT cells compared to non-MAIT CD8+ T cells to define the transcriptome of MAIT cells in the human lung. We show that, as a population, lung MAIT cells are polycytotoxic, secrete the directly antimicrobial molecule IL-26, express genes associated with persistence, and selectively express cytokine and chemokine- related molecules distinct from other lung-resident CD8+ T cells, such as interferon-γ- and IL-12- receptors. These data highlight MAIT cells' predisposition to rapid pro-inflammatory cytokine responsiveness and antimicrobial mechanisms in human lung tissue, concordant with findings of blood-derived counterparts, and support a function for MAIT cells as early sensors in the defense of respiratory barrier function.
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Affiliation(s)
- Erin W Meermeier
- Department of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, OR, 97239, USA
- Department of Medicine, Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, 85259, USA
| | - Christina L Zheng
- Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Jessica G Tran
- VA Portland Health Care System, Portland, OR, 97239, USA
| | - Shogo Soma
- Department of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Aneta H Worley
- VA Portland Health Care System, Portland, OR, 97239, USA
| | - David I Weiss
- David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Robert L Modlin
- Division of Dermatology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Gwendolyn Swarbrick
- Department of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, OR, 97239, USA
- VA Portland Health Care System, Portland, OR, 97239, USA
| | - Elham Karamooz
- Department of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, OR, 97239, USA
- VA Portland Health Care System, Portland, OR, 97239, USA
| | - Sharon Khuzwayo
- Africa Health Research Institute, Durban, South Africa
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Emily B Wong
- Africa Health Research Institute, Durban, South Africa
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
- Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Division of Infection and Immunity, University College London, London, UK
| | - Marielle C Gold
- Department of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, OR, 97239, USA
- VA Portland Health Care System, Portland, OR, 97239, USA
| | - David M Lewinsohn
- Department of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, OR, 97239, USA.
- VA Portland Health Care System, Portland, OR, 97239, USA.
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Frascoli M, Reboldi A, Kang J. Dietary Cholesterol Metabolite Regulation of Tissue Immune Cell Development and Function. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:645-653. [PMID: 35961669 PMCID: PMC10215006 DOI: 10.4049/jimmunol.2200273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 06/14/2022] [Indexed: 01/04/2023]
Abstract
Obesity is considered the primary environmental factor associated with morbidity and severity of wide-ranging inflammatory disorders. The molecular mechanism linking high-fat or cholesterol diet to imbalances in immune responses, beyond the increased production of generic inflammatory factors, is just beginning to emerge. Diet cholesterol by-products are now known to regulate function and migration of diverse immune cell subsets in tissues. The hydroxylated metabolites of cholesterol oxysterols as central regulators of immune cell positioning in lymphoid and mucocutaneous tissues is the focus of this review. Dedicated immunocyte cell surface receptors sense spatially distributed oxysterol tissue depots to tune cell metabolism and function, to achieve the "right place at the right time" axiom of efficient tissue immunity.
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Affiliation(s)
- Michela Frascoli
- Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA
| | - Andrea Reboldi
- Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA
| | - Joonsoo Kang
- Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA
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34
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MAIT cells and their implication in human oral diseases. Inflamm Res 2022; 71:1041-1054. [PMID: 35781343 DOI: 10.1007/s00011-022-01600-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 06/08/2022] [Accepted: 06/09/2022] [Indexed: 11/05/2022] Open
Abstract
OBJECTIVE Mucosal-associated invariant T (MAIT) cells are unique innate-like T cells that are abundant in humans, accounting for 1-10% of circulating T cells and about 2% of total T cells in human oral cavity. MAIT cells can mount a strong immune response quickly without exogenous antigens and undergo a phenotypic transformation in the development of diseases. They produce cytokines involved in the Th1 and Th17 immune response and cytotoxic proteins, promote the dysfunction of autoreactive B cell and inhibit the function of NK cells. MAIT cells have been widely explored in autoimmune diseases, inflammatory diseases and tumors, and these mechanisms may also be involved in the pathogenesis of some oral diseases, while MAIT cells have not been systematically discussed in oral diseases. METHODS We searched PubMed/MEDLINE, EMBASE and Microsoft Bing databases to review and analyze relevant literatures on the impact of MAIT cells in the pathogenesis of human oral diseases. CONCLUSION Collected evidence elucidated the characteristics of MAIT cells and emphasized the potential roles of MAIT cells in oral lichen planus (OLP), chronic graft-versus-host disease (cGVHD), oral squamous cell carcinoma (OSCC), apical periodontitis (AP) and primary Sjogren's syndrome (pSS).
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Gandecha H, Kaur A, Sanghera R, Preece J, Pillay T. Nutrition and Immunity in Perinatal Hypoxic-Ischemic Injury. Nutrients 2022; 14:nu14132747. [PMID: 35807927 PMCID: PMC9269416 DOI: 10.3390/nu14132747] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/23/2022] [Accepted: 06/28/2022] [Indexed: 02/01/2023] Open
Abstract
Perinatal hypoxia ischaemia (PHI), acute and chronic, may be associated with considerable adverse outcomes in the foetus and neonate. The molecular and cellular mechanisms of injury and repair associated with PHI in the perinate are not completely understood. Increasing evidence is mounting for the role of nutrients and bioactive food components in immune development, function and repair in PHI. In this review, we explore current concepts around the neonatal immune response to PHI with a specific emphasis on the impact of nutrition in the mother, foetus and neonate.
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Affiliation(s)
- Hema Gandecha
- Department of Neonatology, University Hospitals Leicester NHS Trust, Leicester LE1 5WW, UK
- East Midlands Deanery, Health Education England, Leicester LE3 5DR, UK
| | - Avineet Kaur
- Department of Neonatology, University Hospitals Leicester NHS Trust, Leicester LE1 5WW, UK
- East Midlands Deanery, Health Education England, Leicester LE3 5DR, UK
| | - Ranveer Sanghera
- Department of Neonatology, University Hospitals Leicester NHS Trust, Leicester LE1 5WW, UK
- East Midlands Deanery, Health Education England, Leicester LE3 5DR, UK
| | - Joanna Preece
- Department of Neonatology, University Hospitals Leicester NHS Trust, Leicester LE1 5WW, UK
| | - Thillagavathie Pillay
- Department of Neonatology, University Hospitals Leicester NHS Trust, Leicester LE1 5WW, UK
- Faculty of Science and Engineering, Research Institute for Healthcare Sciences, University of Wolverhampton, Wolverhampton WV1 1LY, UK
- College of Life Sciences, University of Leicester, Leicester LE5 4PW, UK
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36
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Miko E, Csaszar A, Bodis J, Kovacs K. The Maternal-Fetal Gut Microbiota Axis: Physiological Changes, Dietary Influence, and Modulation Possibilities. Life (Basel) 2022; 12:424. [PMID: 35330175 PMCID: PMC8955030 DOI: 10.3390/life12030424] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 02/07/2023] Open
Abstract
The prenatal period and the first years of life have a significant impact on the health issues and life quality of an individual. The appropriate development of the immune system and the central nervous system are thought to be major critical determining events. In parallel to these, establishing an early intestinal microbiota community is another important factor for future well-being interfering with prenatal and postnatal developmental processes. This review aims at summarizing the main characteristics of maternal gut microbiota and its possible transmission to the offspring, thereby affecting fetal and/or neonatal development and health. Since maternal dietary factors are potential modulators of the maternal-fetal microbiota axis, we will outline current knowledge on the impact of certain diets, nutritional factors, and nutritional modulators during pregnancy on offspring's microbiota and health.
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Affiliation(s)
- Eva Miko
- Department of Medical Microbiology and Immunology, Medical School, University of Pécs, 12 Szigeti Street, 7624 Pécs, Hungary
- National Laboratory for Human Reproduction, University of Pécs, 7624 Pécs, Hungary; (A.C.); (J.B.); (K.K.)
- Janos Szentagothai Research Centre, 20 Ifjusag Street, 7624 Pécs, Hungary
| | - Andras Csaszar
- National Laboratory for Human Reproduction, University of Pécs, 7624 Pécs, Hungary; (A.C.); (J.B.); (K.K.)
- Department of Obstetrics and Gynaecology, Medical School, University of Pécs, 17 Edesanyak Street, 7624 Pécs, Hungary
| | - Jozsef Bodis
- National Laboratory for Human Reproduction, University of Pécs, 7624 Pécs, Hungary; (A.C.); (J.B.); (K.K.)
- Department of Obstetrics and Gynaecology, Medical School, University of Pécs, 17 Edesanyak Street, 7624 Pécs, Hungary
| | - Kalman Kovacs
- National Laboratory for Human Reproduction, University of Pécs, 7624 Pécs, Hungary; (A.C.); (J.B.); (K.K.)
- Department of Obstetrics and Gynaecology, Medical School, University of Pécs, 17 Edesanyak Street, 7624 Pécs, Hungary
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37
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Li Y, Du J, Wei W. Emerging Roles of Mucosal-Associated Invariant T Cells in Rheumatology. Front Immunol 2022; 13:819992. [PMID: 35317168 PMCID: PMC8934402 DOI: 10.3389/fimmu.2022.819992] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 02/14/2022] [Indexed: 12/22/2022] Open
Abstract
Mucosal-associated invariant T (MAIT) cells are an unconventional T cell subset expressing a semi-invariant TCR and recognize microbial riboflavin metabolites presented by major histocompatibility complex class 1-related molecule (MR1). MAIT cells serve as innate-like T cells bridging innate and adaptive immunity, which have attracted increasing attention in recent years. The involvement of MAIT cells has been described in various infections, autoimmune diseases and malignancies. In this review, we first briefly introduce the biology of MAIT cells, and then summarize their roles in rheumatic diseases including systemic lupus erythematosus, rheumatoid arthritis, primary Sjögren’s syndrome, psoriatic arthritis, systemic sclerosis, vasculitis and dermatomyositis. An increased knowledge of MAIT cells will inform the development of novel biomarkers and therapeutic approaches in rheumatology.
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38
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Su B, Kong D, Yang X, Zhang T, Kuang YQ. Mucosal-associated invariant T cells: a cryptic coordinator in HIV-infected immune reconstitution. J Med Virol 2022; 94:3043-3053. [PMID: 35243649 DOI: 10.1002/jmv.27696] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 02/20/2022] [Accepted: 03/01/2022] [Indexed: 11/11/2022]
Abstract
Human immunodeficiency virus type 1 (HIV-1) infection causes considerable morbidity and mortality worldwide. Although antiretroviral therapy (ART) has largely transformed HIV infection from a fatal disease to a chronic condition, approximately 10%~40% of HIV-infected individuals who receive effective ART and sustain long-term viral suppression still cannot achieve optimal immune reconstitution. These patients are called immunological non-responders, a state associated with poor clinical prognosis. Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved unconventional T cell subset defined by expression of semi-invariant αβ T cell receptor (TCR), which recognizes metabolites derived from the riboflavin biosynthetic pathway presented on major histocompatibility complex (MHC)-related protein-1 (MR1). MAIT cells, which are considered to act as a bridge between innate and adaptive immunity, produce a wide range of cytokines and cytotoxic molecules upon activation through TCR-dependent and TCR-independent mechanisms, which is of major importance in defense against a variety of pathogens. In addition, MAIT cells are involved in autoimmune and immune-mediated diseases. The number of MAIT cells is dramatically and irreversibly decreased in the early stage of HIV infection and is not fully restored even after long-term suppressive ART. In light of the important role of MAIT cells in mucosal immunity and because microbial translocation is inversely associated with CD4+ T cell counts, we propose that MAIT cells participate in the maintenance of intestinal barrier integrity and microbial homeostasis, thus further affecting immune reconstitution in HIV-infected individuals. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Bin Su
- Beijing Key Laboratory for HIV/AIDS Research, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.,Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Deshenyue Kong
- NHC Key Laboratory of Drug Addiction Medicine, First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, 650032, China.,Scientific Research Laboratory Center, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Xiaodong Yang
- Beijing Key Laboratory for HIV/AIDS Research, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.,Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Tong Zhang
- Beijing Key Laboratory for HIV/AIDS Research, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.,Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Yi-Qun Kuang
- NHC Key Laboratory of Drug Addiction Medicine, First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, 650032, China.,Scientific Research Laboratory Center, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
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39
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Zhang X, Xu Z, Wen X, Huang G, Nian S, Li L, Guo X, Ye Y, Yuan Q. The onset, development and pathogenesis of severe neutrophilic asthma. Immunol Cell Biol 2022; 100:144-159. [PMID: 35080788 DOI: 10.1111/imcb.12522] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 12/02/2021] [Accepted: 01/23/2022] [Indexed: 12/12/2022]
Abstract
Bronchial asthma is divided into Th2 high, Th2 low and mixed types. The Th2 high type is dominated by eosinophils while the Th2 low type is divided into neutrophilic and paucigranulocytic types. Eosinophilic asthma has gained increased attention recently, and its pathogenesis and treatment are well understood. However, severe neutrophilic asthma requires more in-depth research because its pathogenesis is not well understood, and no effective treatment exists. This review looks at the advances made in asthma research, the pathogenesis of neutrophilic asthma, the mechanisms of progression to severe asthma, risk factors for asthma exacerbations, and biomarkers and treatment of neutrophilic asthma. The pathogenesis of neutrophilic asthma is further discussed from four aspects: Th17-type inflammatory response, inflammasomes, exosomes and microRNAs. This review provides direction for the mechanistic study, diagnosis and treatment of neutrophilic asthma. The treatment of neutrophilic asthma remains a significant challenge for clinical therapists and is an important area of future clinical research.
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Affiliation(s)
- Xingli Zhang
- Public Center of Experimental Technology, Immune Mechanism and Therapy of Major Diseases of Luzhou Key Laboratory, School of Basic Medical Science of Southwest Medical University, Luzhou, Sichuan, China
| | - Zixi Xu
- Public Center of Experimental Technology, Immune Mechanism and Therapy of Major Diseases of Luzhou Key Laboratory, School of Basic Medical Science of Southwest Medical University, Luzhou, Sichuan, China
| | - Xue Wen
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan, China
| | - Guoping Huang
- Zigong Hospital of Woman and Children Healthcare, Sichuan, China
| | - Siji Nian
- Public Center of Experimental Technology, Immune Mechanism and Therapy of Major Diseases of Luzhou Key Laboratory, School of Basic Medical Science of Southwest Medical University, Luzhou, Sichuan, China
| | - Lin Li
- Public Center of Experimental Technology, Immune Mechanism and Therapy of Major Diseases of Luzhou Key Laboratory, School of Basic Medical Science of Southwest Medical University, Luzhou, Sichuan, China
| | - Xiyuan Guo
- Public Center of Experimental Technology, Immune Mechanism and Therapy of Major Diseases of Luzhou Key Laboratory, School of Basic Medical Science of Southwest Medical University, Luzhou, Sichuan, China
| | - Yingchun Ye
- Public Center of Experimental Technology, Immune Mechanism and Therapy of Major Diseases of Luzhou Key Laboratory, School of Basic Medical Science of Southwest Medical University, Luzhou, Sichuan, China
| | - Qing Yuan
- Public Center of Experimental Technology, Immune Mechanism and Therapy of Major Diseases of Luzhou Key Laboratory, School of Basic Medical Science of Southwest Medical University, Luzhou, Sichuan, China
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40
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Mao T, Yang R, Luo Y, He K. Crucial role of T cells in NAFLD-related disease: A review and prospect. Front Endocrinol (Lausanne) 2022; 13:1051076. [PMID: 36457551 PMCID: PMC9705593 DOI: 10.3389/fendo.2022.1051076] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 10/20/2022] [Indexed: 11/17/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) includes a series of hepatic manifestations, starting with liver steatosis and potentially evolving towards nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis or even hepatocellular carcinoma (HCC). Its incidence is increasing worldwide. Several factors including metabolic dysfunction, oxidative stress, lipotoxicity contribute to the liver inflammation. Several immune cell-mediated inflammatory processes are involved in NAFLD in which T cells play a crucial part in the progression of the disease. In this review, we focus on the role of different subsets of both conventional and unconventional T cells in pathogenesis of NAFLD. Factors regarding inflammation and potential therapeutic approaches targeting immune cells in NASH are also discussed.
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Affiliation(s)
- Tianyu Mao
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China
- Shanghai Institute of Transplantation, Shanghai, China
| | - Rui Yang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China
- Shanghai Institute of Transplantation, Shanghai, China
| | - Yi Luo
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China
- Shanghai Institute of Transplantation, Shanghai, China
- *Correspondence: Kang He, ; Yi Luo,
| | - Kang He
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China
- Shanghai Institute of Transplantation, Shanghai, China
- *Correspondence: Kang He, ; Yi Luo,
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41
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Feyaerts D, Urbschat C, Gaudillière B, Stelzer IA. Establishment of tissue-resident immune populations in the fetus. Semin Immunopathol 2022; 44:747-766. [PMID: 35508672 PMCID: PMC9067556 DOI: 10.1007/s00281-022-00931-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 03/17/2022] [Indexed: 12/15/2022]
Abstract
The immune system establishes during the prenatal period from distinct waves of stem and progenitor cells and continuously adapts to the needs and challenges of early postnatal and adult life. Fetal immune development not only lays the foundation for postnatal immunity but establishes functional populations of tissue-resident immune cells that are instrumental for fetal immune responses amidst organ growth and maturation. This review aims to discuss current knowledge about the development and function of tissue-resident immune populations during fetal life, focusing on the brain, lung, and gastrointestinal tract as sites with distinct developmental trajectories. While recent progress using system-level approaches has shed light on the fetal immune landscape, further work is required to describe precise roles of prenatal immune populations and their migration and adaptation to respective organ environments. Defining points of prenatal susceptibility to environmental challenges will support the search for potential therapeutic targets to positively impact postnatal health.
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Affiliation(s)
- Dorien Feyaerts
- grid.168010.e0000000419368956Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA USA
| | - Christopher Urbschat
- grid.13648.380000 0001 2180 3484Division of Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg, Hamburg, Germany
| | - Brice Gaudillière
- grid.168010.e0000000419368956Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA USA ,grid.168010.e0000000419368956Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA USA
| | - Ina A. Stelzer
- grid.168010.e0000000419368956Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA USA
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42
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Constantinides MG, Belkaid Y. Early-life imprinting of unconventional T cells and tissue homeostasis. Science 2021; 374:eabf0095. [PMID: 34882451 DOI: 10.1126/science.abf0095] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Michael G Constantinides
- Metaorganism Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA
| | - Yasmine Belkaid
- Metaorganism Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.,NIAID Microbiome Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA
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43
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Charmetant X, Bachelet T, Déchanet-Merville J, Walzer T, Thaunat O. Innate (and Innate-like) Lymphoid Cells: Emerging Immune Subsets With Multiple Roles Along Transplant Life. Transplantation 2021; 105:e322-e336. [PMID: 33859152 DOI: 10.1097/tp.0000000000003782] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Transplant immunology is currently largely focused on conventional adaptive immunity, particularly T and B lymphocytes, which have long been considered as the only cells capable of allorecognition. In this vision, except for the initial phase of ischemia/reperfusion, during which the role of innate immune effectors is well established, the latter are largely considered as "passive" players, recruited secondarily to amplify graft destruction processes during rejection. Challenging this prevalent dogma, the recent progresses in basic immunology have unraveled the complexity of the innate immune system and identified different subsets of innate (and innate-like) lymphoid cells. As most of these cells are tissue-resident, they are overrepresented among passenger leukocytes. Beyond their role in ischemia/reperfusion, some of these subsets have been shown to be capable of allorecognition and/or of regulating alloreactive adaptive responses, suggesting that these emerging immune players are actively involved in most of the life phases of the grafts and their recipients. Drawing upon the inventory of the literature, this review synthesizes the current state of knowledge of the role of the different innate (and innate-like) lymphoid cell subsets during ischemia/reperfusion, allorecognition, and graft rejection. How these subsets also contribute to graft tolerance and the protection of chronically immunosuppressed patients against infectious and cancerous complications is also examined.
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Affiliation(s)
- Xavier Charmetant
- CIRI, INSERM U1111, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon I, Lyon, France
| | - Thomas Bachelet
- Clinique Saint-Augustin-CTMR, ELSAN, Bordeaux, France
- Department of Nephrology, Transplantation, Dialysis and Apheresis, Bordeaux University Hospital, Bordeaux, France
| | | | - Thierry Walzer
- CIRI, INSERM U1111, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon I, Lyon, France
| | - Olivier Thaunat
- CIRI, INSERM U1111, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon I, Lyon, France
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
- Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
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Vazquez J, Chavarria M, Chasman DA, Schwartz RW, Tyler CT, Lopez G, Fisher RC, Ong IM, Stanic AK. Multiomic analysis reveals decidual-specific transcriptional programing of MAIT cells. Am J Reprod Immunol 2021; 86:e13495. [PMID: 34411378 PMCID: PMC8720468 DOI: 10.1111/aji.13495] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 06/24/2021] [Accepted: 08/16/2021] [Indexed: 12/26/2022] Open
Abstract
PROBLEM Mucosal-Associated Invariant T (MAIT) cells have been recently identified at the maternal-fetal interface. However, transcriptional programming of decidual MAIT cells in pregnancy remains poorly understood. METHOD OF STUDY We employed a multiomic approach to address this question. Mononuclear cells from the decidua basalis and parietalis, and control PBMCs, were analyzed via flow cytometry to investigate MAIT cells in the decidua and assess their transcription factor expression. In a separate study, both decidual and matched peripheral MAIT cells were analyzed using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) coupled with gene expression analysis. Lastly, decidual MAIT cells were stimulated with E.coli and expression of MR1 by antigen presenting cells was measured to evaluate decidual MAIT cell function. RESULTS First, we identified MAIT cells in both the decidua basalis and parietalis. CITE-seq, coupled with scRNA-seq gene expression analysis, highlighted transcriptional programming differences between decidual and matched peripheral MAIT cells at a single cell resolution. Transcription factor expression analysis further highlighted transcriptional differences between decidual MAIT cells and non-matched peripheral MAIT cells. Functionally, MAIT cells are skewed towards IFNγ and TNFα production upon stimulation, with E.coli leading to IFNγ production. Lastly, we demonstrate that MR1, the antigen presenting molecule restricting MAIT cells, is expressed by decidual APCs. CONCLUSION MAIT cells are present in the decidua basalis and obtain a unique gene expression profile. The presence of MR1 on APCs coupled with in vitro activation by E.coli suggests that MAIT cells might be involved in tissue-repair mechanisms at the maternal-fetal interface.
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Affiliation(s)
| | | | - Deborah A. Chasman
- Departments of Obstetrics and Gynecology
- Biostatistics and Medical Informatics
| | - Rene Welch Schwartz
- Departments of Obstetrics and Gynecology
- Biostatistics and Medical Informatics
| | | | | | | | - Irene M. Ong
- Departments of Obstetrics and Gynecology
- Biostatistics and Medical Informatics
- University of Wisconsin Carbone Comprehensive Cancer Center
- Center for Human Genomics and Precision Medicine, University of Wisconsin-Madison, Madison, WI
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Naidoo K, Woods K, Pellefigues C, Cait A, O'Sullivan D, Gell K, Marshall AJ, Anderson RJ, Li Y, Schmidt A, Prasit K, Mayer JU, Gestin A, Hermans IF, Painter G, Jacobsen EA, Gasser O. MR1-dependent immune surveillance of the skin contributes to pathogenesis and is a photobiological target of UV light therapy in a mouse model of atopic dermatitis. Allergy 2021; 76:3155-3170. [PMID: 34185885 DOI: 10.1111/all.14994] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 05/09/2021] [Accepted: 05/24/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Mucosal-associated invariant T (MAIT) cells are unconventional T cells which recognize microbial metabolites presented by the major histocompatibility complex class I-related molecule MR1. Although MAIT cells have been shown to reside in human and murine skin, their contribution to atopic dermatitis (AD), an inflammatory skin disease associated with barrier dysfunction and microbial translocation, has not yet been determined. METHODS Genetic deletion of MR1 and topical treatment with inhibitory MR1 ligands, which result in the absence and functional inhibition of MAIT cells, respectively, were used to investigate the role of MR1-dependent immune surveillance in a MC903-driven murine model of AD. RESULTS The absence or inhibition of MR1 arrested AD disease progression through the blockade of both eosinophil activation and recruitment of IL-4- and IL-13-producing cells. In addition, the therapeutic efficacy of phototherapy against MC903-driven AD could be increased with prior application of folate, which photodegrades into the inhibitory MR1 ligand 6-formylpterin. CONCLUSION We identified MAIT cells as sentinels and mediators of cutaneous type 2 immunity. Their pathogenic activity can be inhibited by topical application or endogenous generation, via phototherapy, of inhibitory MR1 ligands.
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Affiliation(s)
- Karmella Naidoo
- Malaghan Institute of Medical Research Wellington New Zealand
| | - Katherine Woods
- Malaghan Institute of Medical Research Wellington New Zealand
| | | | - Alissa Cait
- Malaghan Institute of Medical Research Wellington New Zealand
| | - David O'Sullivan
- Malaghan Institute of Medical Research Wellington New Zealand
- High‐Value Nutrition National Science Challenge Auckland New Zealand
| | - Katie Gell
- Malaghan Institute of Medical Research Wellington New Zealand
| | - Andrew J. Marshall
- Ferrier Research Institute Victoria University of Wellington Lower Hutt New Zealand
| | - Regan J. Anderson
- Ferrier Research Institute Victoria University of Wellington Lower Hutt New Zealand
| | - Yanyan Li
- Malaghan Institute of Medical Research Wellington New Zealand
- High‐Value Nutrition National Science Challenge Auckland New Zealand
| | - Alfonso Schmidt
- Malaghan Institute of Medical Research Wellington New Zealand
| | - Kef Prasit
- Malaghan Institute of Medical Research Wellington New Zealand
| | | | - Aurelie Gestin
- Malaghan Institute of Medical Research Wellington New Zealand
| | - Ian F. Hermans
- Malaghan Institute of Medical Research Wellington New Zealand
| | - Gavin Painter
- Ferrier Research Institute Victoria University of Wellington Lower Hutt New Zealand
| | - Elizabeth A. Jacobsen
- Division of Allergy, Asthma and Clinical Immunology Mayo Clinic Arizona Scottsdale AZ USA
| | - Olivier Gasser
- Malaghan Institute of Medical Research Wellington New Zealand
- High‐Value Nutrition National Science Challenge Auckland New Zealand
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Czaja AJ. Incorporating mucosal-associated invariant T cells into the pathogenesis of chronic liver disease. World J Gastroenterol 2021; 27:3705-3733. [PMID: 34321839 PMCID: PMC8291028 DOI: 10.3748/wjg.v27.i25.3705] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 03/22/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
Mucosal-associated invariant T (MAIT) cells have been described in liver and non-liver diseases, and they have been ascribed antimicrobial, immune regulatory, protective, and pathogenic roles. The goals of this review are to describe their biological properties, indicate their involvement in chronic liver disease, and encourage investigations that clarify their actions and therapeutic implications. English abstracts were identified in PubMed by multiple search terms, and bibliographies were developed. MAIT cells are activated by restricted non-peptides of limited diversity and by multiple inflammatory cytokines. Diverse pro-inflammatory, anti-inflammatory, and immune regulatory cytokines are released; infected cells are eliminated; and memory cells emerge. Circulating MAIT cells are hyper-activated, immune exhausted, dysfunctional, and depleted in chronic liver disease. This phenotype lacks disease-specificity, and it does not predict the biological effects. MAIT cells have presumed protective actions in chronic viral hepatitis, alcoholic hepatitis, non-alcoholic fatty liver disease, primary sclerosing cholangitis, and decompensated cirrhosis. They have pathogenic and pro-fibrotic actions in autoimmune hepatitis and mixed actions in primary biliary cholangitis. Local factors in the hepatic microenvironment (cytokines, bile acids, gut-derived bacterial antigens, and metabolic by-products) may modulate their response in individual diseases. Investigational manipulations of function are warranted to establish an association with disease severity and outcome. In conclusion, MAIT cells constitute a disease-nonspecific, immune response to chronic liver inflammation and infection. Their pathological role has been deduced from their deficiencies during active liver disease, and future investigations must clarify this role, link it to outcome, and explore therapeutic interventions.
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Affiliation(s)
- Albert J Czaja
- Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, United States
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Rahman Qazi K, Jensen GB, van der Heiden M, Björkander S, Marchini G, Jenmalm MC, Abrahamsson T, Sverremark-Ekström E. Extreme prematurity and sepsis strongly influence frequencies and functional characteristics of circulating γδ T and natural killer cells. Clin Transl Immunology 2021; 10:e1294. [PMID: 34136218 PMCID: PMC8192243 DOI: 10.1002/cti2.1294] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 02/11/2021] [Accepted: 05/17/2021] [Indexed: 12/19/2022] Open
Abstract
Objectives Extremely low gestational age neonates with extremely low birthweight (ELGAN/ELBW) are highly susceptible to infection. This is linked to their relatively immature immune system which is not yet fully compatible with an extra‐uterine environment. Here, we performed a longitudinal characterisation of unconventional T and natural killer (NK) cells in ELGAN/ELBW during their first months of life. Methods Peripheral blood mononuclear cells were collected from 97 ELGAN/ELBW at 14 and 28 days of life and at a time point corresponding to postmenstrual week 36 + 0. γδ T‐cell, NKT‐cell, mucosa‐associated invariant T‐cell and NK cell frequencies and characteristics were analysed by flow cytometry. As control, cells from 14‐day‐old full‐term (FT) infants were included. Results Extreme prematurity had significant bearing on γδ T‐cell and NK cell frequencies and characteristics. ELGAN/ELBW had significantly higher proportions of γδ T cells that were skewed towards effector and effector memory phenotypes, characteristics that were maintained throughout the study period. Expression of the gut homing receptor CCR9 was also more common in γδ T cells from ELGAN/ELBW. Conversely, NK cell frequencies were markedly lower and skewed towards a cytotoxic phenotype in the ELGAN/ELBW group at 14 days of age. Culture‐proven sepsis with an onset during the first 14 days after birth further manifested these differences in the γδ T‐ and NK cell populations at 14 days of age. Conclusion Prematurity strongly influences the levels of γδ T and NK cells, in particular in cases where sepsis debuts during the first 2 weeks of life.
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Affiliation(s)
- Khaleda Rahman Qazi
- Department of Molecular Biosciences The Wenner-Gren Institute Stockholm University Stockholm Sweden
| | - Georg B Jensen
- Department of Biomedical and Clinical Sciences Linköping University Linköping Sweden.,Department of Paediatrics Linköping University Linköping Sweden
| | - Marieke van der Heiden
- Department of Molecular Biosciences The Wenner-Gren Institute Stockholm University Stockholm Sweden
| | - Sophia Björkander
- Department of Molecular Biosciences The Wenner-Gren Institute Stockholm University Stockholm Sweden
| | - Giovanna Marchini
- Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
| | - Maria C Jenmalm
- Department of Biomedical and Clinical Sciences Linköping University Linköping Sweden
| | - Thomas Abrahamsson
- Department of Biomedical and Clinical Sciences Linköping University Linköping Sweden.,Department of Paediatrics Linköping University Linköping Sweden
| | - Eva Sverremark-Ekström
- Department of Molecular Biosciences The Wenner-Gren Institute Stockholm University Stockholm Sweden
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Zubeidat K, Hovav AH. Shaped by the epithelium - postnatal immune mechanisms of oral homeostasis. Trends Immunol 2021; 42:622-634. [PMID: 34083119 DOI: 10.1016/j.it.2021.05.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/05/2021] [Accepted: 05/06/2021] [Indexed: 02/07/2023]
Abstract
The first encounter of mucosal barriers with the microbiota initiates host-microbiota feedback loops instructing the tailored development of both the immune system and microbiota at each mucosal site. Once established, balanced immunological interactions enable symbiotic relationships with the microbiota in adult life. This process has been extensively investigated in the mammalian monolayer epithelium-covered intestine and lung mucosae; however, the postnatal mechanisms engaged by the oral mucosa to establish homeostasis are currently being discovered. Here, we discuss the early life dialogue between the oral mucosa and the microbiota, with particular emphasis on the central role the multilayer epithelium plays to protect the oral mucosa. These intricate and unique postnatal immunological processes shape oral homeostasis, which can potentially affect buccal and systemic health in adult life.
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Affiliation(s)
- Khaled Zubeidat
- The Institute of Biomedical and Oral Research, Faculty of Dental Medicine, Hebrew University, Jerusalem, Israel
| | - Avi-Hai Hovav
- The Institute of Biomedical and Oral Research, Faculty of Dental Medicine, Hebrew University, Jerusalem, Israel.
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Kalbermatter C, Fernandez Trigo N, Christensen S, Ganal-Vonarburg SC. Maternal Microbiota, Early Life Colonization and Breast Milk Drive Immune Development in the Newborn. Front Immunol 2021; 12:683022. [PMID: 34054875 PMCID: PMC8158941 DOI: 10.3389/fimmu.2021.683022] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022] Open
Abstract
The innate immune system is the oldest protection strategy that is conserved across all organisms. Although having an unspecific action, it is the first and fastest defense mechanism against pathogens. Development of predominantly the adaptive immune system takes place after birth. However, some key components of the innate immune system evolve during the prenatal period of life, which endows the newborn with the ability to mount an immune response against pathogenic invaders directly after birth. Undoubtedly, the crosstalk between maternal immune cells, antibodies, dietary antigens, and microbial metabolites originating from the maternal microbiota are the key players in preparing the neonate’s immunity to the outer world. Birth represents the biggest substantial environmental change in life, where the newborn leaves the protective amniotic sac and is exposed for the first time to a countless variety of microbes. Colonization of all body surfaces commences, including skin, lung, and gastrointestinal tract, leading to the establishment of the commensal microbiota and the maturation of the newborn immune system, and hence lifelong health. Pregnancy, birth, and the consumption of breast milk shape the immune development in coordination with maternal and newborn microbiota. Discrepancies in these fine-tuned microbiota interactions during each developmental stage can have long-term effects on disease susceptibility, such as metabolic syndrome, childhood asthma, or autoimmune type 1 diabetes. In this review, we will give an overview of the recent studies by discussing the multifaceted emergence of the newborn innate immune development in line with the importance of maternal and early life microbiota exposure and breast milk intake.
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Affiliation(s)
- Cristina Kalbermatter
- Universitätsklinik für Viszerale Chirurgie und Medizin, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Nerea Fernandez Trigo
- Universitätsklinik für Viszerale Chirurgie und Medizin, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Sandro Christensen
- Universitätsklinik für Viszerale Chirurgie und Medizin, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Stephanie C Ganal-Vonarburg
- Universitätsklinik für Viszerale Chirurgie und Medizin, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
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Moriarty RV, Ellis AL, O’Connor SL. Monkeying around with MAIT Cells: Studying the Role of MAIT Cells in SIV and Mtb Co-Infection. Viruses 2021; 13:863. [PMID: 34066765 PMCID: PMC8151491 DOI: 10.3390/v13050863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/03/2021] [Accepted: 05/06/2021] [Indexed: 11/25/2022] Open
Abstract
There were an estimated 10 million new cases of tuberculosis (TB) disease in 2019. While over 90% of individuals successfully control Mycobacterium tuberculosis (Mtb) infection, which causes TB disease, HIV co-infection often leads to active TB disease. Despite the co-endemic nature of HIV and TB, knowledge of the immune mechanisms contributing to the loss of control of Mtb replication during HIV infection is lacking. Mucosal-associated invariant T (MAIT) cells are innate-like T cells that target and destroy bacterially-infected cells and may contribute to the control of Mtb infection. Studies examining MAIT cells in human Mtb infection are commonly performed using peripheral blood samples. However, because Mtb infection occurs primarily in lung tissue and lung-associated lymph nodes, these studies may not be fully translatable to the tissues. Additionally, studies longitudinally examining MAIT cell dynamics during HIV/Mtb co-infection are rare, and lung and lymph node tissue samples from HIV+ patients are typically unavailable. Nonhuman primates (NHP) provide a model system to characterize MAIT cell activity during Mtb infection, both in Simian Immunodeficiency Virus (SIV)-infected and SIV-naïve animals. Using NHPs allows for a more comprehensive understanding of tissue-based MAIT cell dynamics during infection with both pathogens. NHP SIV and Mtb infection is similar to human HIV and Mtb infection, and MAIT cells are phenotypically similar in humans and NHPs. Here, we discuss current knowledge surrounding MAIT cells in SIV and Mtb infection, how SIV infection impairs MAIT cell function during Mtb co-infection, and knowledge gaps to address.
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Affiliation(s)
| | | | - Shelby L. O’Connor
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53711, USA; (R.V.M.); (A.L.E.)
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