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Van Acker N, Frenois FX, Gravelle P, Tosolini M, Syrykh C, Laurent C, Brousset P. Spatial mapping of innate lymphoid cells in human lymphoid tissues and lymphoma at single-cell resolution. Nat Commun 2025; 16:4545. [PMID: 40374674 PMCID: PMC12081901 DOI: 10.1038/s41467-025-59811-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 05/06/2025] [Indexed: 05/17/2025] Open
Abstract
Innate lymphoid cells (ILC) distribution and compartmentalization in human lymphoid tissues are incompletely described. Through combined multiplex immunofluorescence, multispectral imaging, and advanced computer vision methods, we provide a map of ILCs at the whole-slide single-cell resolution level, and study their proximity to T helper (Th) cells. The results show that ILC2 predominates in thymic medulla; by contrast, immature Th cells prevail in the cortex. Unexpectedly, we find that Th2-like and Th17-like phenotypes appear before complete T cell receptor gene rearrangements in these immature thymocytes. In the periphery, ILC2 are more abundant in lymph nodes and tonsils, penetrating lymphoid follicles. NK cells are uncommon in lymphoid tissues but abundant in the spleen, whereas ILC1 and ILC3 predominate in the ileum and appendix. Under pathogenic conditions, a deep perturbation of both ILC and Th populations is seen in follicular lymphoma compared with non-neoplastic conditions. Lastly, all ILCs are preferentially in close proximity to their Th counterparts. In summary, our histopathology tool help present a spatial mapping of human ILCs and Th cells, in normal and neoplastic lymphoid tissues.
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Affiliation(s)
- Nathalie Van Acker
- Department of Pathology, CHU of Toulouse, Imag'IN Platform, IUCT-Oncopole, Toulouse, France
- Cancer Research Center of Toulouse (INSERM), Team 9 NoLymIT and Labex TOUCAN, Toulouse, France
| | - François-Xavier Frenois
- Department of Pathology, CHU of Toulouse, Imag'IN Platform, IUCT-Oncopole, Toulouse, France
- Cancer Research Center of Toulouse (INSERM), Team 9 NoLymIT and Labex TOUCAN, Toulouse, France
| | - Pauline Gravelle
- Department of Pathology, CHU of Toulouse, Imag'IN Platform, IUCT-Oncopole, Toulouse, France
- Cancer Research Center of Toulouse (INSERM), Team 9 NoLymIT and Labex TOUCAN, Toulouse, France
| | - Marie Tosolini
- Cancer Research Center of Toulouse (INSERM), Team 9 NoLymIT and Labex TOUCAN, Toulouse, France
| | - Charlotte Syrykh
- Department of Pathology, CHU of Toulouse, Imag'IN Platform, IUCT-Oncopole, Toulouse, France
- Cancer Research Center of Toulouse (INSERM), Team 9 NoLymIT and Labex TOUCAN, Toulouse, France
| | - Camille Laurent
- Department of Pathology, CHU of Toulouse, Imag'IN Platform, IUCT-Oncopole, Toulouse, France
- Cancer Research Center of Toulouse (INSERM), Team 9 NoLymIT and Labex TOUCAN, Toulouse, France
| | - Pierre Brousset
- Department of Pathology, CHU of Toulouse, Imag'IN Platform, IUCT-Oncopole, Toulouse, France.
- Cancer Research Center of Toulouse (INSERM), Team 9 NoLymIT and Labex TOUCAN, Toulouse, France.
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Nouari W, Aribi M. Innate lymphoid cells, immune functional dynamics, epithelial parallels, and therapeutic frontiers in infections. Int Rev Immunol 2025:1-28. [PMID: 40242974 DOI: 10.1080/08830185.2025.2490233] [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: 04/03/2024] [Revised: 02/19/2025] [Accepted: 04/02/2025] [Indexed: 04/18/2025]
Abstract
Innate lymphoid cells (ILCs) have emerged as pivotal players in the field of immunology, expanding our understanding of innate immunity beyond conventional paradigms. This comprehensive review delves into the multifaceted world of ILCs, beginning with their serendipitous discovery and traversing their ontogeny and heterogeneity. We explore the distinct subsets of ILCs unraveling their intriguing plasticity, which adds a layer of complexity to their functional repertoire. As we journey through the functional activities of ILCs, we address their role in immune responses against various infections, categorizing their interactions with helminthic parasites, bacterial pathogens, fungal infections, and viral invaders. Notably, this review offers a detailed examination of ILCs in the context of specific infections, such as Mycobacterium tuberculosis, Citrobacter rodentium, Clostridium difficile, Salmonella typhimurium, Helicobacter pylori, Listeria monocytogenes, Staphylococcus aureus, Pseudomonas aeruginosa, Influenza virus, Cytomegalovirus, Herpes simplex virus, and severe acute respiratory syndrome coronavirus 2. This selection aimed for a comprehensive exploration of ILCs in various infectious contexts, opting for microorganisms based on extensive research findings rather than considerations of virulence or emergence. Furthermore, we raise intriguing questions about the potential immune functional resemblances between ILCs and epithelial cells, shedding light on their interconnectedness within the mucosal microenvironment. The review culminates in a critical assessment of the therapeutic prospects of targeting ILCs during infection, emphasizing their promise as novel immunotherapeutic targets. Nevertheless, due to their recent discovery and evolving understanding, effectively manipulating ILCs is challenging. Ensuring specificity and safety while evaluating long-term effects in clinical settings will be crucial.
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Affiliation(s)
- Wafa Nouari
- Laboratory of Applied Molecular Biology and Immunology, University of Tlemcen, Tlemcen, Algeria
| | - Mourad Aribi
- Laboratory of Applied Molecular Biology and Immunology, University of Tlemcen, Tlemcen, Algeria
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3
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Gatica S, Paillal N, Rangel-Ramírez MA, Méndez L, Fernández-Tello A, Kalergis AM, Bueno SM, González PA, Soto JA, Simon F, Carreño LJ, Melo-Gonzalez F, Riedel CA. Gestational Hypothyroxinemia Shifts Th1/Th17 Immunity and Innate Lymphoid Cell Balance in the Adult Offspring during the Presymptomatic Stage of Experimental Autoimmune Encephalomyelitis. Neuroimmunomodulation 2025; 32:126-138. [PMID: 40209697 DOI: 10.1159/000545578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 03/26/2025] [Indexed: 04/12/2025] Open
Abstract
INTRODUCTION Thyroid hormone homeostasis during pregnancy is crucial for proper neurodevelopment and cognitive capacity during adulthood. Accumulating evidence reveals that gestational hypothyroxinemia (HTX) modulates the immune response of the adult offspring. METHODS In the present study, adult mice gestated in HTX and their euthyroid counterparts were induced with a mild form of experimental autoimmune encephalomyelitis (EAE), a widespread model of multiple sclerosis, and analyzed at baseline and 7 days after EAE induction. RESULTS Levels of circulating IL-17 were significantly lower in mice gestated in HTX at both timepoints, while circulating IFN-γ was significantly higher only in mice gestated in HTX, 7 days after EAE induction. A significant increase in type 1 innate lymphoid cells (ILC1) was found only in mice gestated in HTX 7 days after EAE induction, while type 3 innate lymphoid cells (ILC3) populations showed no variation. Interestingly, a significant increase of Th17 CD4+ cells was found only in mice of euthyroid gestation, 7 days after EAE induction. CONCLUSION These results highlight the repercussions of thyroid hormone impairment in utero at adult ages while dissecting on the pathogenesis of EAE in terms of Th1/Th17 balance from an innate immune perspective. These findings contribute to the advancement of our comprehension of the presymptomatic stage of EAE, unveiling new paths for basic and translational research in the field of neuroinflammation.
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Affiliation(s)
- Sebastian Gatica
- Laboratorio de Endocrino-Inmunología, Centro de Investigación de Resiliencia a Pandemias, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
| | - Nicolas Paillal
- Laboratorio de Endocrino-Inmunología, Centro de Investigación de Resiliencia a Pandemias, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
| | - Ma Andreina Rangel-Ramírez
- Laboratorio de Endocrino-Inmunología, Centro de Investigación de Resiliencia a Pandemias, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
| | - Luis Méndez
- Laboratorio de Endocrino-Inmunología, Centro de Investigación de Resiliencia a Pandemias, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Odontología, Laboratorio de Odontología Traslacional, Universidad Andres Bello, Santiago, Chile
| | - Alonso Fernández-Tello
- Laboratorio de Endocrino-Inmunología, Centro de Investigación de Resiliencia a Pandemias, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
| | - Alexis M Kalergis
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Susan M Bueno
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pablo A González
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Jorge A Soto
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Translational Immunology Laboratory, Centro de Investigación de Resiliencia a Pandemias, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
| | - Felipe Simon
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Laboratorio de Fisiopatología Integrativa, Centro de Investigación de Resiliencia a Pandemias, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
| | - Leandro J Carreño
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Felipe Melo-Gonzalez
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Translational Immunology Laboratory, Centro de Investigación de Resiliencia a Pandemias, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
| | - Claudia A Riedel
- Laboratorio de Endocrino-Inmunología, Centro de Investigación de Resiliencia a Pandemias, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
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Su X, Deng Z, Lan Y, Liu B, Liu C. Helper ILCs in the human hematopoietic system. Trends Immunol 2025; 46:244-257. [PMID: 40011157 DOI: 10.1016/j.it.2025.01.009] [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: 12/10/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/28/2025]
Abstract
Helper innate lymphoid cells (ILCs), comprising groups ILC1, ILC2, and ILC3, possess unique advantages in eliciting rapid immune responses and were recently found to exhibit direct tumor-killing capacities comparable with those of cytotoxic ILCs [natural killer (NK) cells] in humans and mice. Although ILCs are primarily tissue-resident cells, their role in the hematopoietic system is increasingly being recognized. This review provides an overview of ILC ontogeny, as well as the physiological and pathological roles of these cells within the human and murine hematopoietic systems. We recapitulate recent advancements regarding ILC embryonic hematopoietic origin and the dynamic interactions between ILCs and leukemic cells or other immune cell populations, highlighting the dual roles ILCs can play in carcinogenesis. Exploring the functional potential of ILCs can inform the design of rational immunotherapeutic strategies against hematological malignancies.
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Affiliation(s)
- Xiaoyu Su
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang 212013, China
| | - Zhaoqun Deng
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang 212013, China; Department of Oncology, The Second Affiliated Hospital of Jiaxing University, No. 397, Huangcheng North Road, Jiaxing 314000, China.
| | - Yu Lan
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
| | - Bing Liu
- State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Senior Department of Hematology, Fifth Medical Center, Medical Innovation Research Department, Chinese PLA General Hospital, Beijing 100071, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
| | - Chen Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
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5
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Thompson DA, Wabara YB, Duran S, Reichenbach A, Chen L, Collado K, Yon C, Greally DMed JM, Rastogi D. Single cell analysis identifies distinct CD4 + T cells associated with the pathobiology of pediatric obesity related asthma. Sci Rep 2025; 15:6844. [PMID: 40000680 PMCID: PMC11861978 DOI: 10.1038/s41598-025-88423-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 01/28/2025] [Indexed: 02/27/2025] Open
Abstract
Pediatric obesity-related asthma is characterized by non-atopic T helper 1 (Th1) inflammation and steroid resistance. CDC42 upregulation in CD4 + T cells underlies Th1 inflammation but the CD4 + T cell subtype(s) with CDC42 upregulation and their contribution to steroid resistance are not known. Compared to healthy-weight asthma, obesity-alone and healthy-weight controls, single-cell transcriptomics of obese asthma CD4 + T cells revealed CDC42 upregulation in 3 clusters comprised of naïve and central memory T cells, which differed from the cluster enriched for Th1 responses that was comprised of effector T cells. NR3C1, coding for the glucocorticoid receptor, was downregulated, while genes coding for NLRP3 inflammasome were upregulated, in clusters with CDC42 upregulation and Th1 responses. Conserved genes in these clusters correlated with pulmonary function deficits in obese asthma. These findings suggest that several distinct CD4 + T cell subtypes are programmed in obese asthma for CDC42 upregulation, Th1 inflammation, and steroid resistance, and together contribute to the obese asthma phenotype.
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Affiliation(s)
- David A Thompson
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Yvonne B Wabara
- Children's National Hospital, George Washington University, Washington, DC, USA
| | - Sarai Duran
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Anna Reichenbach
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Laura Chen
- Department of Pediatrics, Yale University, New Haven, CT, USA
| | - Kayla Collado
- Montefiore Health System, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Changsuek Yon
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - John M Greally DMed
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
- Montefiore Health System, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Deepa Rastogi
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA.
- Children's Hospital at Montefiore Albert Einstein College of Medicine, 3415 Bainbridge Ave, Bronx, NY, 10467, USA.
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6
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Li X, He J, Gao X, Zheng G, Chen C, Chen Y, Xing Z, Wang T, Tang J, Guo Y, He Y. GPX4 restricts ferroptosis of NKp46 +ILC3s to control intestinal inflammation. Cell Death Dis 2024; 15:687. [PMID: 39300068 PMCID: PMC11413021 DOI: 10.1038/s41419-024-07060-3] [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: 06/19/2024] [Revised: 08/31/2024] [Accepted: 09/05/2024] [Indexed: 09/22/2024]
Abstract
Group 3 innate lymphoid cells (ILC3s) are essential for both pathogen defense and tissue homeostasis in the intestine. Dysfunction of ILC3s could lead to increased susceptibility to intestinal inflammation. However, the precise mechanisms governing the maintenance of intestinal ILC3s are yet to be fully elucidated. Here, we demonstrated that ferroptosis is vital for regulating the survival of intestinal ILC3. Ferroptosis-related genes, including GPX4, a key regulator of ferroptosis, were found to be upregulated in intestinal mucosal ILC3s from ulcerative colitis patients. Deletion of GPX4 resulted in a decrease in NKp46+ILC3 cell numbers, impaired production of IL-22 and IL-17A, and exacerbated intestinal inflammation in a T cell-independent manner. Our mechanistic studies revealed that GPX4-mediated ferroptosis in NKp46+ILC3 cells was regulated by the LCN2-p38-ATF4-xCT signaling pathway. Mice lacking LCN2 in ILC3s or administration of a p38 pathway inhibitor exhibited similar phenotypes of ILC3 and colitis to those observed in GPX4 conditional knock-out mice. These observations provide novel insights into therapeutic strategies for intestinal inflammation by modulating ILC3 ferroptosis.
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Affiliation(s)
- Xinyao Li
- Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences); Department of Immunology, School of Basic Medical Sciences; Department of Clinical Laboratory, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China
- Department of Immunology; Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Junyu He
- Department of Immunology; Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xiang Gao
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Guilang Zheng
- Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University; Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Chunling Chen
- Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University; Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yimin Chen
- Department of Immunology; Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zhe Xing
- Department of Immunology; Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Tianci Wang
- Department of Immunology; Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Jian Tang
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuxiong Guo
- Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University; Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
| | - Yumei He
- Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences); Department of Immunology, School of Basic Medical Sciences; Department of Clinical Laboratory, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China.
- Department of Immunology; Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
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7
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Shen G, Wang Q, Li Z, Xie J, Han X, Wei Z, Zhang P, Zhao S, Wang X, Huang X, Xu M. Bridging Chronic Inflammation and Digestive Cancer: The Critical Role of Innate Lymphoid Cells in Tumor Microenvironments. Int J Biol Sci 2024; 20:4799-4818. [PMID: 39309440 PMCID: PMC11414386 DOI: 10.7150/ijbs.96338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 08/09/2024] [Indexed: 09/25/2024] Open
Abstract
The incidence and mortality of digestive system-related cancers have always been high and attributed to the heterogeneity and complexity of the immune microenvironment of the digestive system. Furthermore, several studies have shown that chronic inflammation in the digestive system is responsible for cancer incidence; therefore, controlling inflammation is a potential strategy to stop the development of cancer. Innate Lymphoid Cells (ILC) represent a heterogeneous group of lymphocytes that exist in contrast to T cells. They function by interacting with cytokines and immune cells in an antigen-independent manner. In the digestive system cancer, from the inflammatory phase to the development, migration, and metastasis of tumors, ILC have been found to interact with the immune microenvironment and either control or promote these processes. The conventional treatments for digestive tumors have limited efficacy, therefore, ILC-associated immunotherapies are promising strategies. This study reviews the characterization of different ILC subpopulations, how they interact with and influence the immune microenvironment as well as chronic inflammation, and their promotional or inhibitory role in four common digestive system tumors, including pancreatic, colorectal, gastric, and hepatocellular cancers. In particular, the review emphasizes the role of ILC in associating chronic inflammation with cancer and the potential for enhanced immunotherapy with cytokine therapy and adoptive immune cell therapy.
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Affiliation(s)
- Guanliang Shen
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, 212001, China
- Digestive Disease Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Qi Wang
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, 212001, China
- Digestive Disease Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Zhengrui Li
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Jiaheng Xie
- Department of Plastic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Xinda Han
- Xinglin College, Nantong University, Nantong, Jiangsu, China
| | - Zehao Wei
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, 212001, China
- Digestive Disease Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Pengpeng Zhang
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Songyun Zhao
- Department of Neurosurgery, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Xiumei Wang
- Affiliated Cancer Hospital of Inner Mongolia Medical University, 010020, Inner Mongolia, China
| | | | - Min Xu
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, 212001, China
- Digestive Disease Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
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8
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Thompson DA, Wabara YB, Duran S, Reichenbach A, Chen L, Collado K, Yon C, Greally JM, Rastogi D. Single-cell analysis identifies distinct CD4+ T cells associated with the pathobiology of pediatric obesity-related asthma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.13.607447. [PMID: 39211259 PMCID: PMC11361012 DOI: 10.1101/2024.08.13.607447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Pediatric obesity-related asthma is characterized by non-atopic T helper 1 (Th1) inflammation and steroid resistance. CDC42 upregulation in CD4+T cells underliesTh1 inflammation but the CD4+T cell subtype(s) with CDC42 upregulation and their contribution to steroid resistance are not known. Compared to healthy-weight asthma, obesity-alone and healthy-weight controls, single-cell transcriptomics of obese asthma CD4+T cells revealed CDC42 upregulation in 3 clusters comprised of naïve and central memory T cells, which differed from the cluster enriched for Th1 responses that was comprised of effector T cells. NR3C1, coding for glucocorticoid receptor, was downregulated, while genes coding for NLRP3 inflammasome were upregulated, in clusters with CDC42 upregulation and Th1 responses. Conserved genes in these clusters correlated with pulmonary function deficits in obese asthma. These findings suggest that several distinct CD4+T cell subtypes are programmed in obese asthma for CDC42 upregulation, Th1 inflammation, and steroid resistance, and together contribute to obese asthma phenotype. Summary CD4+T cells from obese children with asthma are distinctly programmed for non-allergic immune responses, steroid resistance and inflammasome activation, that underlie the obese asthma phenotype.
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9
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Yount KS, Darville T. Immunity to Sexually Transmitted Bacterial Infections of the Female Genital Tract: Toward Effective Vaccines. Vaccines (Basel) 2024; 12:863. [PMID: 39203989 PMCID: PMC11359697 DOI: 10.3390/vaccines12080863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 07/19/2024] [Accepted: 07/27/2024] [Indexed: 09/03/2024] Open
Abstract
Sexually transmitted infections (STIs) caused by bacterial pathogens Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum present significant public health challenges. These infections profoundly impact reproductive health, leading to pelvic inflammatory disease, infertility, and increased susceptibility to other infections. Prevention measures, including antibiotic treatments, are limited by the often-asymptomatic nature of these infections, the need for repetitive and continual screening of sexually active persons, antibiotic resistance for gonorrhea, and shortages of penicillin for syphilis. While vaccines exist for viral STIs like human papillomavirus (HPV) and hepatitis B virus (HBV), there are no vaccines available for bacterial STIs. This review examines the immune responses in the female genital tract to these bacterial pathogens and the implications for developing effective vaccines against bacterial STIs.
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Affiliation(s)
| | - Toni Darville
- Department of Pediatrics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;
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10
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Xing Z, Li X, He J, Chen Y, Zhu L, Zhang X, Huang Z, Tang J, Guo Y, He Y. OLFM4 modulates intestinal inflammation by promoting IL-22 +ILC3 in the gut. Commun Biol 2024; 7:914. [PMID: 39075283 PMCID: PMC11286877 DOI: 10.1038/s42003-024-06601-y] [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: 01/21/2024] [Accepted: 07/18/2024] [Indexed: 07/31/2024] Open
Abstract
Group 3 innate lymphoid cells (ILC3s) play key roles in intestinal inflammation. Olfactomedin 4 (OLFM4) is highly expressed in the colon and has a potential role in dextran sodium sulfate-induced colitis. However, the detailed mechanisms underlying the effects of OLFM4 on ILC3-mediated colitis remain unclear. In this study, we identify OLFM4 as a positive regulator of IL-22+ILC3. OLFM4 expression in colonic ILC3s increases substantially during intestinal inflammation in humans and mice. Compared to littermate controls, OLFM4-deficient (OLFM4-/-) mice are more susceptible to bacterial infection and display greater resistance to anti-CD40 induced innate colitis, together with impaired IL-22 production by ILC3, and ILC3s from OLFM4-/-mice are defective in pathogen resistance. Besides, mice with OLFM4 deficiency in the RORγt compartment exhibit the same trend as in OLFM4-/-mice, including colonic inflammation and IL-22 production. Mechanistically, the decrease in IL-22+ILC3 caused by OLFM4 deficiency involves the apoptosis signal-regulating kinase 1 (ASK1)- p38 MAPK signaling-dependent downregulation of RAR-related orphan receptor gamma (RORγt) protein. The OLFM4-metadherin (MTDH) complex upregulates p38/RORγt signaling, which is necessary for IL-22+ILC3 activation. The findings indicate that OLFM4 is a novel regulator of IL-22+ILC3 and essential for modulating intestinal inflammation and tissue homeostasis.
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Affiliation(s)
- Zhe Xing
- Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences); Department of Immunology, School of Basic Medical Sciences; Department of Clinical Laboratory, the Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China
| | - Xinyao Li
- Department of Immunology; Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences; Southern Medical University, Guangzhou, China
| | - Junyu He
- Department of Immunology; Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences; Southern Medical University, Guangzhou, China
| | - Yimin Chen
- Department of Immunology; Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences; Southern Medical University, Guangzhou, China
| | - Lei Zhu
- Institute of Thoracic Oncology and Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaogang Zhang
- Department of Immunology; Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences; Southern Medical University, Guangzhou, China
| | - Zhengcong Huang
- Department of Immunology; Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences; Southern Medical University, Guangzhou, China
| | - Jian Tang
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Yuxiong Guo
- Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University; Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
| | - Yumei He
- Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences); Department of Immunology, School of Basic Medical Sciences; Department of Clinical Laboratory, the Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China.
- Department of Immunology; Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences; Southern Medical University, Guangzhou, China.
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11
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Sudan R, Gilfillan S, Colonna M. Group 1 ILCs: Heterogeneity, plasticity, and transcriptional regulation. Immunol Rev 2024; 323:107-117. [PMID: 38563448 PMCID: PMC11102297 DOI: 10.1111/imr.13327] [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] [Indexed: 04/04/2024]
Abstract
Group 1 innate lymphoid cells (ILCs), comprising ILC1s and natural killer cells (NK cells), belong to a large family of developmentally related innate lymphoid cells that lack rearranged antigen-specific receptors. NK cells and ILC1s both require the transcription factor T-bet for lineage commitment but additionally rely on Eomes and Hobit, respectively, for their development and effector maturation programs. Both ILC1s and NK cells are essential for rapid responses against infections and mediate cancer immunity through production of effector cytokines and cytotoxicity mediators. ILC1s are enriched in tissues and hence generally considered tissue resident cells whereas NK cells are often considered circulatory. Despite being deemed different cell types, ILC1s and NK cells share many common features both phenotypically and functionally. Recent studies employing single cell RNA sequencing (scRNA-seq) technology have exposed previously unappreciated heterogeneity in group 1 ILCs and further broaden our understanding of these cells. Findings from these studies imply that ILC1s in different tissues and organs share a common signature but exhibit some unique characteristics, possibly stemming from tissue imprinting. Also, data from recent fate mapping studies employing Hobit, RORγt, and polychromic reporter mice have greatly advanced our understanding of the developmental and effector maturation programs of these cells. In this review, we aim to outline the fundamental traits of mouse group 1 ILCs and explore recent discoveries related to their developmental programs, phenotypic heterogeneity, plasticity, and transcriptional regulation.
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Affiliation(s)
- Raki Sudan
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
| | - Susan Gilfillan
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
| | - Marco Colonna
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
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12
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To TT, Oparaugo NC, Kheshvadjian AR, Nelson AM, Agak GW. Understanding Type 3 Innate Lymphoid Cells and Crosstalk with the Microbiota: A Skin Connection. Int J Mol Sci 2024; 25:2021. [PMID: 38396697 PMCID: PMC10888374 DOI: 10.3390/ijms25042021] [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: 12/01/2023] [Revised: 01/18/2024] [Accepted: 01/26/2024] [Indexed: 02/25/2024] Open
Abstract
Innate lymphoid cells (ILCs) are a diverse population of lymphocytes classified into natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and ILCregs, broadly following the cytokine secretion and transcription factor profiles of classical T cell subsets. Nonetheless, the ILC lineage does not have rearranged antigen-specific receptors and possesses distinct characteristics. ILCs are found in barrier tissues such as the skin, lungs, and intestines, where they play a role between acquired immune cells and myeloid cells. Within the skin, ILCs are activated by the microbiota and, in turn, may influence the microbiome composition and modulate immune function through cytokine secretion or direct cellular interactions. In particular, ILC3s provide epithelial protection against extracellular bacteria. However, the mechanism by which these cells modulate skin health and homeostasis in response to microbiome changes is unclear. To better understand how ILC3s function against microbiota perturbations in the skin, we propose a role for these cells in response to Cutibacterium acnes, a predominant commensal bacterium linked to the inflammatory skin condition, acne vulgaris. In this article, we review current evidence describing the role of ILC3s in the skin and suggest functional roles by drawing parallels with ILC3s from other organs. We emphasize the limited understanding and knowledge gaps of ILC3s in the skin and discuss the potential impact of ILC3-microbiota crosstalk in select skin diseases. Exploring the dialogue between the microbiota and ILC3s may lead to novel strategies to ameliorate skin immunity.
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Affiliation(s)
- Thao Tam To
- Division of Dermatology, Department of Medicine, University of California (UCLA), Los Angeles, CA 90095, USA
| | - Nicole Chizara Oparaugo
- Division of Dermatology, Department of Medicine, University of California (UCLA), Los Angeles, CA 90095, USA
| | - Alexander R. Kheshvadjian
- Division of Dermatology, Department of Medicine, University of California (UCLA), Los Angeles, CA 90095, USA
| | - Amanda M. Nelson
- Department of Dermatology, Penn State University College of Medicine, Hershey, PA 17033, USA
| | - George W. Agak
- Division of Dermatology, Department of Medicine, University of California (UCLA), Los Angeles, CA 90095, USA
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13
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Wang J, Gao M, Cheng M, Luo J, Lu M, Xing X, Sun Y, Lu Y, Li X, Shi C, Wang J, Wang N, Yang W, Jiang Y, Huang H, Yang G, Zeng Y, Wang C, Cao X. Single-Cell Transcriptional Analysis of Lamina Propria Lymphocytes in the Jejunum Reveals Innate Lymphoid Cell-like Cells in Pigs. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:130-142. [PMID: 37975680 DOI: 10.4049/jimmunol.2300463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 10/20/2023] [Indexed: 11/19/2023]
Abstract
Pigs are the most suitable model to study various therapeutic strategies and drugs for human beings, although knowledge about cell type-specific transcriptomes and heterogeneity is poorly available. Through single-cell RNA sequencing and flow cytometry analysis of the types in the jejunum of pigs, we found that innate lymphoid cells (ILCs) existed in the lamina propria lymphocytes (LPLs) of the jejunum. Then, through flow sorting of live/dead-lineage (Lin)-CD45+ cells and single-cell RNA sequencing, we found that ILCs in the porcine jejunum were mainly ILC3s, with a small number of NK cells, ILC1s, and ILC2s. ILCs coexpressed IL-7Rα, ID2, and other genes and differentially expressed RORC, GATA3, and other genes but did not express the CD3 gene. ILC3s can be divided into four subgroups, and genes such as CXCL8, CXCL2, IL-22, IL-17, and NCR2 are differentially expressed. To further detect and identify ILC3s, we verified the classification of ILCs in the porcine jejunum subgroup and the expression of related hallmark genes at the protein level by flow cytometry. For systematically characterizing ILCs in the porcine intestines, we combined our pig ILC dataset with publicly available human and mice ILC data and identified that the human and pig ILCs shared more common features than did those mouse ILCs in gene signatures and cell states. Our results showed in detail for the first time (to our knowledge) the gene expression of porcine jejunal ILCs, the subtype classification of ILCs, and the markers of various ILCs, which provide a basis for an in-depth exploration of porcine intestinal mucosal immunity.
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Affiliation(s)
- Junhong Wang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Ming Gao
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Mingyang Cheng
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Jiawei Luo
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Mei Lu
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Xinyuan Xing
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Yu Sun
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Yiyuan Lu
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Xiaoxu Li
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Chunwei Shi
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Jianzhong Wang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Nan Wang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Wentao Yang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Yanlong Jiang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Haibin Huang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Guilian Yang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Yan Zeng
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Chunfeng Wang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Xin Cao
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China; and Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Jilin Agricultural University, Changchun, China
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14
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Ryu S, Lim M, Kim J, Kim HY. Versatile roles of innate lymphoid cells at the mucosal barrier: from homeostasis to pathological inflammation. Exp Mol Med 2023; 55:1845-1857. [PMID: 37696896 PMCID: PMC10545731 DOI: 10.1038/s12276-023-01022-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/31/2023] [Accepted: 04/04/2023] [Indexed: 09/13/2023] Open
Abstract
Innate lymphoid cells (ILCs) are innate lymphocytes that do not express antigen-specific receptors and largely reside and self-renew in mucosal tissues. ILCs can be categorized into three groups (ILC1-3) based on the transcription factors that direct their functions and the cytokines they produce. Their signature transcription factors and cytokines closely mirror those of their Th1, Th2, and Th17 cell counterparts. Accumulating studies show that ILCs are involved in not only the pathogenesis of mucosal tissue diseases, especially respiratory diseases, and colitis, but also the resolution of such diseases. Here, we discuss recent advances regarding our understanding of the biology of ILCs in mucosal tissue health and disease. In addition, we describe the current research on the immune checkpoints by which other cells regulate ILC activities: for example, checkpoint molecules are potential new targets for therapies that aim to control ILCs in mucosal diseases. In addition, we review approved and clinically- trialed drugs and drugs in clinical trials that can target ILCs and therefore have therapeutic potential in ILC-mediated diseases. Finally, since ILCs also play important roles in mucosal tissue homeostasis, we explore the hitherto sparse research on cell therapy with regulatory ILCs. This review highlights various therapeutic approaches that could be used to treat ILC-mediated mucosal diseases and areas of research that could benefit from further investigation.
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Affiliation(s)
- Seungwon Ryu
- Department of Microbiology, Gachon University College of Medicine, Incheon, 21999, South Korea
| | - MinYeong Lim
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, South Korea
- CIRNO, Sungkyunkwan University, Suwon, South Korea
| | - Jinwoo Kim
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, South Korea
- CIRNO, Sungkyunkwan University, Suwon, South Korea
| | - Hye Young Kim
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea.
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, South Korea.
- CIRNO, Sungkyunkwan University, Suwon, South Korea.
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15
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Long XQ, Liu MZ, Liu ZH, Xia LZ, Lu SP, Xu XP, Wu MH. Bile acids and their receptors: Potential therapeutic targets in inflammatory bowel disease. World J Gastroenterol 2023; 29:4252-4270. [PMID: 37545642 PMCID: PMC10401658 DOI: 10.3748/wjg.v29.i27.4252] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 05/19/2023] [Accepted: 06/21/2023] [Indexed: 07/13/2023] Open
Abstract
Chronic and recurrent inflammatory disorders of the gastrointestinal tract caused by a complex interplay between genetics and intestinal dysbiosis are called inflammatory bowel disease. As a result of the interaction between the liver and the gut microbiota, bile acids are an atypical class of steroids produced in mammals and traditionally known for their function in food absorption. With the development of genomics and metabolomics, more and more data suggest that the pathophysiological mechanisms of inflammatory bowel disease are regulated by bile acids and their receptors. Bile acids operate as signalling molecules by activating a variety of bile acid receptors that impact intestinal flora, epithelial barrier function, and intestinal immunology. Inflammatory bowel disease can be treated in new ways by using these potential molecules. This paper mainly discusses the increasing function of bile acids and their receptors in inflammatory bowel disease and their prospective therapeutic applications. In addition, we explore bile acid metabolism and the interaction of bile acids and the gut microbiota.
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Affiliation(s)
- Xiong-Quan Long
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Ming-Zhu Liu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Zi-Hao Liu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Lv-Zhou Xia
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Shi-Peng Lu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Xiao-Ping Xu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Ming-Hao Wu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
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16
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Grifoni A, Alonzi T, Alter G, Noonan DM, Landay AL, Albini A, Goletti D. Impact of aging on immunity in the context of COVID-19, HIV, and tuberculosis. Front Immunol 2023; 14:1146704. [PMID: 37292210 PMCID: PMC10246744 DOI: 10.3389/fimmu.2023.1146704] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 05/11/2023] [Indexed: 06/10/2023] Open
Abstract
Knowledge of aging biology needs to be expanded due to the continuously growing number of elderly people worldwide. Aging induces changes that affect all systems of the body. The risk of cardiovascular disease and cancer increases with age. In particular, the age-induced adaptation of the immune system causes a greater susceptibility to infections and contributes to the inability to control pathogen growth and immune-mediated tissue damage. Since the impact of aging on immune function, is still to be fully elucidated, this review addresses some of the recent understanding of age-related changes affecting key components of immunity. The emphasis is on immunosenescence and inflammaging that are impacted by common infectious diseases that are characterized by a high mortality, and includes COVID-19, HIV and tuberculosis.
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Affiliation(s)
- Alba Grifoni
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA, United States
| | - Tonino Alonzi
- Translational Research Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, Rome, Italy
| | - Galit Alter
- Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), and Harvard, Cambridge, MA, United States
| | - Douglas McClain Noonan
- Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Alan L. Landay
- Department of Internal Medicine, Rush Medical College, Chicago, IL, United States
| | | | - Delia Goletti
- Translational Research Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, Rome, Italy
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17
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Schroeder JH, Beattie G, Lo JW, Zabinski T, Powell N, Neves JF, Jenner RG, Lord GM. CD90 is not constitutively expressed in functional innate lymphoid cells. Front Immunol 2023; 14:1113735. [PMID: 37114052 PMCID: PMC10126679 DOI: 10.3389/fimmu.2023.1113735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 02/28/2023] [Indexed: 04/29/2023] Open
Abstract
Huge progress has been made in understanding the biology of innate lymphoid cells (ILC) by adopting several well-known concepts in T cell biology. As such, flow cytometry gating strategies and markers, such as CD90, have been applied to indentify ILC. Here, we report that most non-NK intestinal ILC have a high expression of CD90 as expected, but surprisingly a sub-population of cells exhibit low or even no expression of this marker. CD90-negative and CD90-low CD127+ ILC were present amongst all ILC subsets in the gut. The frequency of CD90-negative and CD90-low CD127+ ILC was dependent on stimulatory cues in vitro and enhanced by dysbiosis in vivo. CD90-negative and CD90-low CD127+ ILC were a potential source of IL-13, IFNγ and IL-17A at steady state and upon dysbiosis- and dextran sulphate sodium-elicited colitis. Hence, this study reveals that, contrary to expectations, CD90 is not constitutively expressed by functional ILC in the gut.
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Affiliation(s)
- Jan-Hendrik Schroeder
- School of Immunology and Microbial Sciences, King’s College London, London, United Kingdom
| | - Gordon Beattie
- Cancer Research UK (CRUK) City of London Centre Single Cell Genomics Facility, University College London Cancer Institute, University College London (UCL), London, United Kingdom
- Genomics Translational Technology Platform, University College London (UCL) Cancer Institute, University College London, London, United Kingdom
| | - Jonathan W. Lo
- School of Immunology and Microbial Sciences, King’s College London, London, United Kingdom
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Tomasz Zabinski
- School of Immunology and Microbial Sciences, King’s College London, London, United Kingdom
| | - Nick Powell
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Joana F. Neves
- School of Immunology and Microbial Sciences, King’s College London, London, United Kingdom
| | - Richard G. Jenner
- University College London (UCL) Cancer Institute, University College London, London, United Kingdom
| | - Graham M. Lord
- School of Immunology and Microbial Sciences, King’s College London, London, United Kingdom
- School of Biological Sciences, Faculty of Biology, Medicine and Health, Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, United Kingdom
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18
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Zhang Y, Feng X, Chen J, Liu J, Wu J, Tan H, Mi Z, Rong P. Controversial role of ILC3s in intestinal diseases: A novelty perspective on immunotherapy. Front Immunol 2023; 14:1134636. [PMID: 37063879 PMCID: PMC10090672 DOI: 10.3389/fimmu.2023.1134636] [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: 12/30/2022] [Accepted: 03/13/2023] [Indexed: 03/31/2023] Open
Abstract
ILC3s have been identified as crucial immune regulators that play a role in maintaining host homeostasis and modulating the antitumor response. Emerging evidence supports the idea that LTi cells play an important role in initiating lymphoid tissue development, while other ILC3s can promote host defense and orchestrate adaptive immunity, mainly through the secretion of specific cytokines and crosstalk with other immune cells or tissues. Additionally, dysregulation of ILC3-mediated overexpression of cytokines, changes in subset abundance, and conversion toward other ILC subsets are closely linked with the occurrence of tumors and inflammatory diseases. Regulation of ILC3 cytokines, ILC conversion and LTi-induced TLSs may be a novel strategy for treating tumors and intestinal or extraintestinal inflammatory diseases. Herein, we discuss the development of ILCs, the biology of ILC3s, ILC plasticity, the correlation of ILC3s and adaptive immunity, crosstalk with the intestinal microenvironment, controversial roles of ILC3s in intestinal diseases and potential applications for treatment.
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Affiliation(s)
- Yunshu Zhang
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Xuefei Feng
- Department of Government & Public Administration, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Juan Chen
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jiahao Liu
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jianmin Wu
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hongpei Tan
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ze Mi
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- *Correspondence: Ze Mi, ; Pengfei Rong,
| | - Pengfei Rong
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, Hunan, China
- *Correspondence: Ze Mi, ; Pengfei Rong,
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Korchagina AA, Shein SA, Koroleva E, Tumanov AV. Transcriptional control of ILC identity. Front Immunol 2023; 14:1146077. [PMID: 36969171 PMCID: PMC10033543 DOI: 10.3389/fimmu.2023.1146077] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 02/21/2023] [Indexed: 03/12/2023] Open
Abstract
Innate lymphoid cells (ILCs) are heterogeneous innate immune cells which participate in host defense, mucosal repair and immunopathology by producing effector cytokines similarly to their adaptive immune cell counterparts. The development of ILC1, 2, and 3 subsets is controlled by core transcription factors: T-bet, GATA3, and RORγt, respectively. ILCs can undergo plasticity and transdifferentiate to other ILC subsets in response to invading pathogens and changes in local tissue environment. Accumulating evidence suggests that the plasticity and the maintenance of ILC identity is controlled by a balance between these and additional transcription factors such as STATs, Batf, Ikaros, Runx3, c-Maf, Bcl11b, and Zbtb46, activated in response to lineage-guiding cytokines. However, how interplay between these transcription factors leads to ILC plasticity and the maintenance of ILC identity remains hypothetical. In this review, we discuss recent advances in understanding transcriptional regulation of ILCs in homeostatic and inflammatory conditions.
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Korchagina AA, Koroleva E, Tumanov AV. Innate Lymphoid Cell Plasticity in Mucosal Infections. Microorganisms 2023; 11:461. [PMID: 36838426 PMCID: PMC9967737 DOI: 10.3390/microorganisms11020461] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/06/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
Mucosal tissue homeostasis is a dynamic process that involves multiple mechanisms including regulation of innate lymphoid cells (ILCs). ILCs are mostly tissue-resident cells which are critical for tissue homeostasis and immune response against pathogens. ILCs can sense environmental changes and rapidly respond by producing effector cytokines to limit pathogen spread and initiate tissue recovery. However, dysregulation of ILCs can also lead to immunopathology. Accumulating evidence suggests that ILCs are dynamic population that can change their phenotype and functions under rapidly changing tissue microenvironment. However, the significance of ILC plasticity in response to pathogens remains poorly understood. Therefore, in this review, we discuss recent advances in understanding the mechanisms regulating ILC plasticity in response to intestinal, respiratory and genital tract pathogens. Key transcription factors and lineage-guiding cytokines regulate this plasticity. Additionally, we discuss the emerging data on the role of tissue microenvironment, gut microbiota, and hypoxia in ILC plasticity in response to mucosal pathogens. The identification of new pathways and molecular mechanisms that control functions and plasticity of ILCs could uncover more specific and effective therapeutic targets for infectious and autoimmune diseases where ILCs become dysregulated.
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Affiliation(s)
| | | | - Alexei V. Tumanov
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA
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