|
1
|
Liu S, Wang M, Xu L, Deng D, Lu L, Tian J, Zhou D, Rui K. New insight into the role of SOCS family in immune regulation and autoimmune pathogenesis. J Adv Res 2025:S2090-1232(25)00313-3. [PMID: 40349956 DOI: 10.1016/j.jare.2025.05.020] [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: 11/20/2024] [Revised: 04/07/2025] [Accepted: 05/08/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Suppressor of cytokine signaling (SOCS) proteins regulate signal transduction by interacting with cytokine receptors and signaling proteins and targeting associated proteins for degradation. Recent studies have demonstrated that the SOCS proteins serve as crucial inhibitors in cytokine signaling networks and play a pivotal role in both innate and adaptive immune responses. AIM OF REVIEW In this review, we aim to discuss recent advancements in understanding the complex functions of SOCS proteins in various immune cells, as well as the effects of SOCS proteins in human health and diseases. Increasing evidence indicates that SOCS proteins are frequently dysregulated in developing autoimmune diseases, suggesting that therapeutic targeting of SOCS proteins could provide clinical benefit. KEY SCIENTIFIC CONCEPTS OF REVIEW This review provides a comprehensive understanding of SOCS proteins in immune regulation and autoimmune pathogenesis, it also highlights the role of SOCS-related mimetic peptides in immunotherapy.
Collapse
Affiliation(s)
- Shiyi Liu
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China; Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Mingwei Wang
- Department of Emergency, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Liangjie Xu
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Daihua Deng
- Department of Rheumatology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Liwei Lu
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Chongqing International Institute for Immunology, China
| | - Jie Tian
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China.
| | - Dongmei Zhou
- Department of Rheumatology and Immunology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
| | - Ke Rui
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
| |
Collapse
|
|
2
|
Maru SY, Wetzel M, Mitchell JT, Gross NE, Andaloori L, Howe K, Kartalia E, Mo G, Leatherman J, Ho WJ, Fertig EJ, Kagohara LT, Pearce EJ, Jaffee EM. Antigen-presenting cancer-associated fibroblasts in murine pancreatic tumors differentially control regulatory T cell phenotype and function via CXCL9 and CCL22. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.27.645833. [PMID: 40236227 PMCID: PMC11996409 DOI: 10.1101/2025.03.27.645833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a complex tumor microenvironment (TME) including stromal cells that influence resistance to therapy. Recent studies have revealed that stromal cancer-associated fibroblasts (CAFs) are heterogeneous in origin, gene expression, and function. Antigen-presenting CAFs (apCAFs), are defined by major histocompatibility complex (MHC)-II expression and can activate effector CD4 + T cells that have the potential to contribute to the anti-cancer immune response, but also can induce regulatory T cell (Treg) differentiation. Whether apCAFs promote or restrain the antitumor response remains uncertain. Using tumor clones of the KPC murine PDAC model differing in sensitivity to immune checkpoint blockade (ICB), we found that immunosensitive (sKPC) tumors were characterized by higher immune cell and apCAF infiltration than resistant (rKPC) tumors. IMC analysis showed proximity of apCAFs and CD4 + T cells in both sKPC and rKPC tumors implicating interaction within the TME. apCAF-depleted sKPC tumor-bearing mice had diminished sensitivity to ICB. apCAFs from both sKPC and rKPC tumors activated tumor-infiltrating CD4 + T cells and induced Treg differentiation. However, transcriptomic analysis showed that Tregs induced by apCAFs were overexpressed for immunosuppressive genes in rKPCs relative to sKPCs, and that this is associated with differential chemokine signaling from apCAFs depending on tumor origin. Together these data implicate apCAFs as important mediators of the antitumor immune response, modulation of which could facilitate the development of more effective anti-tumor immune based approaches for PDAC patients.
Collapse
|
|
3
|
Xin Y, Yang M, Zhao Z, He Z, Mei Y, Xiong F, Tan F, Chen A, Chang C, Dai H, Wu H, Lu Q. AIM2 deficiency in CD4 + T cells promotes psoriasis-like inflammation by regulating Th17-Treg axis via AIM2-IKZF2 pathway. J Autoimmun 2025; 150:103351. [PMID: 39689661 DOI: 10.1016/j.jaut.2024.103351] [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: 10/12/2024] [Revised: 11/28/2024] [Accepted: 12/06/2024] [Indexed: 12/19/2024]
Abstract
Psoriasis vulgaris remains a common inflammatory skin disease globally. The imbalance between Th17 and Treg cells plays an integral role in the pathogenesis of psoriasis vulgaris, but the underlying mechanisms remain obscure. The role of AIM2 in Treg cell function in psoriasis is unclear. We found that AIM2 expression is upregulated in peripheral blood and skin lesions from patients with psoriasis vulgaris when compared with healthy controls. In a psoriasis-like mouse model, CD4creAim2fl/fl mice showed aggravated psoriatic symptoms, increased Th17 cell and decreased Treg cell numbers in spleens and dLNs compared to Aim2fl/fl mice. The loss of AIM2 in naïve CD4+ T cells promotes Th17 cell differentiation and decreases Treg cell numbers in vitro. Further, IKZF2 was identified as a downstream regulator of AIM2 through RNAseq analysis. AIM2 deficiency in CD4+ T cells downregulated IKZF2 mRNA expression. Silencing IKZF2 in naïve CD4+ T cells led to a significant increase in the expression of RORc and diminished FOXP3 expression. In summary, AIM2 may regulate the differentiation of Th17 and Treg cell by affecting IKZF2. Our findings might shed light on the pathogenesis of psoriasis and provide potential therapeutic targets for patients with psoriasis.
Collapse
Affiliation(s)
- Yue Xin
- Department of Dermatology, the Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China
| | - Ming Yang
- Department of Dermatology, the Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China
| | - Zhidan Zhao
- Department of Dermatology, the Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China
| | - Zhenghao He
- Department of Plastic Surgery, Zhongshan City People's Hospital, Zhongshan, Guangdong, China
| | - Yang Mei
- Department of Dermatology, the Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China
| | - Feng Xiong
- Department of Dermatology, the Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China
| | - Fen Tan
- Department of Dermatology, the Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China
| | - Anqun Chen
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Christopher Chang
- Division of Immunology, Allergy and Pediatric Rheumatology, Joe DiMaggio Children's Hospital, Memorial Healthcare System, Hollywood, FL, 33021, USA
| | - Helong Dai
- Department of Kidney Transplantation, Center of Organ Transplantation, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Haijing Wu
- Department of Dermatology, the Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China; The Furong Laboratory, Changsha, Hunan, China.
| | - Qianjin Lu
- Department of Dermatology, the Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China; Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, China.
| |
Collapse
|
|
4
|
Hetemäki I, Arstila TP, Kekäläinen E. Helios-Illuminating the way for lymphocyte self-control. Immunology 2025; 174:17-29. [PMID: 39354708 PMCID: PMC11652420 DOI: 10.1111/imm.13866] [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: 08/10/2024] [Accepted: 09/11/2024] [Indexed: 10/03/2024] Open
Abstract
Transcription factor Helios, encoded by the IKZF2 gene, has an important role in regulatory T cells by stabilizing their suppressive phenotype. While Helios is prominently expressed in regulatory T cells, its expression extends beyond to include effector T cells, follicular regulatory T cells, B cells, and innate-like lymphocyte populations. Recent characterizations of patients with inborn error of immunity due to damaging IKZF2 variants coupled with translational research on lymphocytes from healthy individuals, have increased our understanding on Helios' multifaceted role in controlling the human adaptive immune system. A less studied role for Helios beyond the stabilizing of regulatory T cells has emerged in directing effector T cell maturation. In the absence of functional Helios, effector T cells acquire more inflammatory phenotype and are prone to senescence. Loss of Helios expression disrupts the regulation of the germinal centre reaction, often resulting in either hypogammaglobulinemia or B cell autoimmunity. This review summarizes findings from studies in both mice and men offering a comprehensive understanding of the impact of the transcription factor Helios on the adaptive immune system.
Collapse
Affiliation(s)
- Iivo Hetemäki
- Translational Immunology Research ProgramUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
| | - T. Petteri Arstila
- Translational Immunology Research ProgramUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
| | - Eliisa Kekäläinen
- Translational Immunology Research ProgramUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
| |
Collapse
|
|
5
|
Ichiyama K, Long J, Kobayashi Y, Horita Y, Kinoshita T, Nakamura Y, Kominami C, Georgopoulos K, Sakaguchi S. Transcription factor Ikzf1 associates with Foxp3 to repress gene expression in Treg cells and limit autoimmunity and anti-tumor immunity. Immunity 2024; 57:2043-2060.e10. [PMID: 39111316 DOI: 10.1016/j.immuni.2024.07.010] [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: 08/10/2023] [Revised: 02/16/2024] [Accepted: 07/15/2024] [Indexed: 09/13/2024]
Abstract
The master transcription factor of regulatory T (Treg) cells, forkhead box protein P3 (Foxp3), controls Treg cell function by targeting certain genes for activation or repression, but the specific mechanisms by which it mediates this activation or repression under different conditions remain unclear. We found that Ikzf1 associates with Foxp3 via its exon 5 (IkE5) and that IkE5-deficient Treg cells highly expressed genes that would otherwise be repressed by Foxp3 upon T cell receptor stimulation, including Ifng. Treg-specific IkE5-deletion caused interferon-γ (IFN-γ) overproduction, which destabilized Foxp3 expression and impaired Treg suppressive function, leading to systemic autoimmune disease and strong anti-tumor immunity. Pomalidomide, which degrades IKZF1 and IKZF3, induced IFN-γ overproduction in human Treg cells. Mechanistically, the Foxp3-Ikzf1-Ikzf3 complex competed with epigenetic co-activators, such as p300, for binding to target gene loci via chromatin remodeling. Therefore, the Ikzf1 association with Foxp3 is essential for the gene-repressive function of Foxp3 and could be exploited to treat autoimmune disease and cancer.
Collapse
Affiliation(s)
- Kenji Ichiyama
- Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
| | - Jia Long
- Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
| | - Yusuke Kobayashi
- Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; Department of Medical Innovations, Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Osaka, Japan
| | - Yuji Horita
- Joint Research Chair of Immune-therapeutic Drug Discovery, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; Department of Research Management, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Takeshi Kinoshita
- Joint Research Chair of Immune-therapeutic Drug Discovery, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; Department of Research Management, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Yamami Nakamura
- Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
| | - Chizuko Kominami
- Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
| | - Katia Georgopoulos
- Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
| | - Shimon Sakaguchi
- Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; Department of Experimental Pathology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
| |
Collapse
|
|
6
|
Chowdhary K, Léon J, Mathis D, Benoist C. An integrated transcription factor framework for Treg identity and diversity. Proc Natl Acad Sci U S A 2024; 121:e2411301121. [PMID: 39196621 PMCID: PMC11388289 DOI: 10.1073/pnas.2411301121] [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: 06/05/2024] [Accepted: 07/12/2024] [Indexed: 08/29/2024] Open
Abstract
Vertebrate cell identity depends on the combined activity of scores of transcription factors (TF). While TFs have often been studied in isolation, a systematic perspective on their integration has been missing. Focusing on FoxP3+ regulatory T cells (Tregs), key guardians of immune tolerance, we combined single-cell chromatin accessibility, machine learning, and high-density genetic variation, to resolve a validated framework of diverse Treg chromatin programs, each shaped by multi-TF inputs. This framework identified previously unrecognized Treg controllers (Smarcc1) and illuminated the mechanism of action of FoxP3, which amplified a pre-existing Treg identity, diversely activating or repressing distinct programs, dependent on different regulatory partners. Treg subpopulations in the colon relied variably on FoxP3, Helios+ Tregs being completely dependent, but RORγ+ Tregs largely independent. These differences were rooted in intrinsic biases decoded by the integrated framework. Moving beyond master regulators, this work unravels how overlapping TF activities coalesce into Treg identity and diversity.
Collapse
Affiliation(s)
| | - Juliette Léon
- Department of Immunology, Harvard Medical School, Boston, MA 02115
- INSERM UMR 1163, Imagine Institute, University of Paris, Paris, France 75015
| | - Diane Mathis
- Department of Immunology, Harvard Medical School, Boston, MA 02115
| | | |
Collapse
|
|
7
|
Vakrakou AG, Kourepini E, Skordos I, Nieto N, Panoutsakopoulou V, Paschalidis N. Osteopontin Regulates Treg Cell Stability and Function with Implications for Anti-Tumor Immunity and Autoimmunity. Cancers (Basel) 2024; 16:2952. [PMID: 39272810 PMCID: PMC11393878 DOI: 10.3390/cancers16172952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/16/2024] [Accepted: 08/20/2024] [Indexed: 09/15/2024] Open
Abstract
Foxp3-expressing regulatory T (Treg) cells represent the most highly immunosuppressive cell in the tumor microenvironment (TME) that halts effective anti-tumor immunity. Osteopontin (Opn), an extracellular matrix (ECM) glycophosphoprotein, plays key roles in many types of immune-related diseases and is associated with cancer aggressiveness when expressed by tumor cells. However, its role in Foxp3Treg heterogeneity, function, and stability in the TME is poorly defined. We generated mice with a Foxp3-specific deletion of Opn and assessed the ability of Opn-deficient Tregs to suppress inflammation. As these mice aged, they developed a scurfy-like syndrome characterized by aberrant and excessive activation of effector T cells. We evaluated and further confirmed the reduced suppressive capacity of Opn-deficient Tregs in an in vivo suppression assay of colitis. We also found that mice with Opn-deficient Foxp3+ Tregs have enhanced anti-tumor immunity and reduced tumor burden, associated with an unstable Treg phenotype, paralleled by reduced Foxp3 expression in tumor-infiltrating lymphocytes. Finally, we observed reduced Foxp3 and Helios expression in Opn-deficient Tregs compared to wild-type controls after in vitro activation. Our findings indicate that targeting Opn in Tregs reveals vigorous and effective ways of promoting Treg instability and dysfunction in the TME, facilitating anti-tumor immunity.
Collapse
Affiliation(s)
- Aigli G Vakrakou
- Laboratory of Neuroimmunology, First Department of Neurology, Aeginition Hospital, National and Kapodistrian, University of Athens, 21 Papadiamantopoulou, Ilisia, 11528 Athens, Greece
| | - Evangelia Kourepini
- Biomedical Research Foundation, Academy of Athens, 4 Soranou Efessiou Street, 11527 Athens, Greece
| | - Ioannis Skordos
- Biomedical Research Foundation, Academy of Athens, 4 Soranou Efessiou Street, 11527 Athens, Greece
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Vily Panoutsakopoulou
- Biomedical Research Foundation, Academy of Athens, 4 Soranou Efessiou Street, 11527 Athens, Greece
| | - Nikolaos Paschalidis
- Biomedical Research Foundation, Academy of Athens, 4 Soranou Efessiou Street, 11527 Athens, Greece
| |
Collapse
|
|
8
|
Gootjes C, Zwaginga JJ, Roep BO, Nikolic T. Defining Human Regulatory T Cells beyond FOXP3: The Need to Combine Phenotype with Function. Cells 2024; 13:941. [PMID: 38891073 PMCID: PMC11172350 DOI: 10.3390/cells13110941] [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: 02/28/2024] [Revised: 04/18/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Regulatory T cells (Tregs) are essential to maintain immune homeostasis by promoting self-tolerance. Reduced Treg numbers or functionality can lead to a loss of tolerance, increasing the risk of developing autoimmune diseases. An overwhelming variety of human Tregs has been described, based on either specific phenotype, tissue compartment, or pathological condition, yet the bulk of the literature only addresses CD25-positive and CD127-negative cells, coined by naturally occurring Tregs (nTregs), most of which express the transcription factor Forkhead box protein 3 (FOXP3). While the discovery of FOXP3 was seminal to understanding the origin and biology of nTregs, there is evidence in humans that not all T cells expressing FOXP3 are regulatory, and that not all Tregs express FOXP3. Namely, the activation of human T cells induces the transient expression of FOXP3, irrespective of whether they are regulatory or inflammatory effectors, while some induced T cells that may be broadly defined as Tregs (e.g., Tr1 cells) typically lack demethylation and do not express FOXP3. Furthermore, it is unknown whether and how many nTregs exist without FOXP3 expression. Several other candidate regulatory molecules, such as GITR, Lag-3, GARP, GPA33, Helios, and Neuropilin, have been identified but subsequently discarded as Treg-specific markers. Multiparametric analyses have uncovered a plethora of Treg phenotypes, and neither single markers nor combinations thereof can define all and only Tregs. To date, only the functional capacity to inhibit immune responses defines a Treg and distinguishes Tregs from inflammatory T cells (Teffs) in humans. This review revisits current knowledge of the Treg universe with respect to their heterogeneity in phenotype and function. We propose that it is unavoidable to characterize human Tregs by their phenotype in combination with their function, since phenotype alone does not unambiguously define Tregs. There is an unmet need to align the expression of specific markers or combinations thereof with a particular suppressive function to coin functional Treg entities and categorize Treg diversity.
Collapse
Affiliation(s)
- Chelsea Gootjes
- Laboratory of Immunomodulation and Regenerative Cell Therapy, Department of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (J.J.Z.); (T.N.)
| | | | | | | |
Collapse
|
|
9
|
Zhang YS, Chen YQ. Dysfunctional regulatory T cell: May be an obstacle to immunotherapy in cardiovascular diseases. Biomed Pharmacother 2024; 173:116359. [PMID: 38430633 DOI: 10.1016/j.biopha.2024.116359] [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: 12/06/2023] [Revised: 02/18/2024] [Accepted: 02/26/2024] [Indexed: 03/05/2024] Open
Abstract
Inflammatory responses are linked to cardiovascular diseases (CVDs) in various forms. Tregs, members of CD4+ T cells, play important roles in regulating immune system and suppressing inflammatory response, thus contributing to maintaining immune homeostasis. However, Tregs exert their powerful suppressive function relying on the stable phenotype and function. The stability of Tregs primarily depends on the FOXP3 (Forkhead box P3) expression and epigenetic regulation. Although Tregs are quite stable under physiological conditions, prolonged exposure to inflammatory cues, Tregs may lose suppressive function and require proinflammatory phenotype, namely plastic Tregs or ex-Tregs. There are extensive researches have established the beneficial role of Tregs in CVDs. Nevertheless, the potential risks of dysfunctional Tregs lack deep research. Anti-inflammatory and immunological modulation have been hotspots in the treatment of CVDs. Tregs are appealing because of their crucial role in resolving inflammation and promoting tissue repair. If alleviating inflammatory response through modulating Tregs could be a new therapeutic strategy for CVDs, the next step to consider is how to prevent the formation of dysfunctional Tregs or reverse detrimental Tregs to normal phenotype.
Collapse
Affiliation(s)
- Yu-Sha Zhang
- Department of Cardiology, the Second Xiangya Hospital, Central South University, Hunan, China
| | - Ya-Qin Chen
- Department of Cardiology, the Second Xiangya Hospital, Central South University, Hunan, China.
| |
Collapse
|
|
10
|
Alvarez F, Liu Z, Bay A, Piccirillo CA. Deciphering the developmental trajectory of tissue-resident Foxp3 + regulatory T cells. Front Immunol 2024; 15:1331846. [PMID: 38605970 PMCID: PMC11007185 DOI: 10.3389/fimmu.2024.1331846] [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: 11/01/2023] [Accepted: 02/14/2024] [Indexed: 04/13/2024] Open
Abstract
Foxp3+ TREG cells have been at the focus of intense investigation for their recognized roles in preventing autoimmunity, facilitating tissue recuperation following injury, and orchestrating a tolerance to innocuous non-self-antigens. To perform these critical tasks, TREG cells undergo deep epigenetic, transcriptional, and post-transcriptional changes that allow them to adapt to conditions found in tissues both at steady-state and during inflammation. The path leading TREG cells to express these tissue-specialized phenotypes begins during thymic development, and is further driven by epigenetic and transcriptional modifications following TCR engagement and polarizing signals in the periphery. However, this process is highly regulated and requires TREG cells to adopt strategies to avoid losing their regulatory program altogether. Here, we review the origins of tissue-resident TREG cells, from their thymic and peripheral development to the transcriptional regulators involved in their tissue residency program. In addition, we discuss the distinct signalling pathways that engage the inflammatory adaptation of tissue-resident TREG cells, and how they relate to their ability to recognize tissue and pathogen-derived danger signals.
Collapse
Affiliation(s)
- Fernando Alvarez
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunology in Global Health Program, The Research Institute of the McGill University Health Centre (RI-MUHC), Montréal, QC, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, QC, Canada
| | - Zhiyang Liu
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunology in Global Health Program, The Research Institute of the McGill University Health Centre (RI-MUHC), Montréal, QC, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, QC, Canada
| | - Alexandre Bay
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunology in Global Health Program, The Research Institute of the McGill University Health Centre (RI-MUHC), Montréal, QC, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, QC, Canada
| | - Ciriaco A. Piccirillo
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunology in Global Health Program, The Research Institute of the McGill University Health Centre (RI-MUHC), Montréal, QC, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, QC, Canada
| |
Collapse
|
|
11
|
McCullough MJ, Tune MK, Cabrera JC, Torres-Castillo J, He M, Feng Y, Doerschuk CM, Dang H, Beltran AS, Hagan RS, Mock JR. Characterization of the MT-2 Treg-like cell line in the presence and absence of forkhead box P3 (FOXP3). Immunol Cell Biol 2024; 102:211-224. [PMID: 38288547 DOI: 10.1111/imcb.12725] [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: 03/22/2023] [Revised: 11/24/2023] [Accepted: 01/08/2024] [Indexed: 03/02/2024]
Abstract
CD4+ forkhead box P3 (FOXP3)+ regulatory T cells (Tregs) are essential in maintaining immune tolerance and suppressing excessive immune responses. Tregs also contribute to tissue repair processes distinct from their roles in immune suppression. For these reasons, Tregs are candidates for targeted therapies for inflammatory and autoimmune diseases, and in diseases where tissue damage occurs. MT-2 cells, an immortalized Treg-like cell line, offer a model to study Treg biology and their therapeutic potential. In the present study, we use clustered regularly interspaced palindromic repeats (CRISPR)-mediated knockdown of FOXP3 in MT-2 cells to understand the transcriptional and functional changes that occur when FOXP3 is lost and to compare MT-2 cells with primary human Tregs. We demonstrate that loss of FOXP3 affects the transcriptome of MT-2 cells and that FOXP3's potential downstream targets include a wide range of transcripts that participate in the cell cycle, promote growth and contribute to inflammatory processes, but do not wholly simulate previously reported human primary Treg transcriptional changes in the absence of FOXP3. We also demonstrate that FOXP3 regulates cell cycling and proliferation, expression of molecules crucial to Treg function and MT-2 cell-suppressive activities. Thus, MT-2 cells offer opportunities to address regulatory T-cell functions in vitro.
Collapse
Affiliation(s)
- Morgan J McCullough
- Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
- Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, USA
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA
| | - Miriya K Tune
- Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
- Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, USA
| | | | - Jose Torres-Castillo
- Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
- Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, USA
| | - Minghong He
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Yongqiang Feng
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Claire M Doerschuk
- Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
- Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, USA
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
- Center for Airways Disease, University of North Carolina, Chapel Hill, NC, USA
| | - Hong Dang
- Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, USA
| | - Adriana S Beltran
- Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Robert S Hagan
- Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
- Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, USA
| | - Jason R Mock
- Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
- Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, USA
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA
| |
Collapse
|
|
12
|
Santosh Nirmala S, Kayani K, Gliwiński M, Hu Y, Iwaszkiewicz-Grześ D, Piotrowska-Mieczkowska M, Sakowska J, Tomaszewicz M, Marín Morales JM, Lakshmi K, Marek-Trzonkowska NM, Trzonkowski P, Oo YH, Fuchs A. Beyond FOXP3: a 20-year journey unravelling human regulatory T-cell heterogeneity. Front Immunol 2024; 14:1321228. [PMID: 38283365 PMCID: PMC10811018 DOI: 10.3389/fimmu.2023.1321228] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 12/19/2023] [Indexed: 01/30/2024] Open
Abstract
The initial idea of a distinct group of T-cells responsible for suppressing immune responses was first postulated half a century ago. However, it is only in the last three decades that we have identified what we now term regulatory T-cells (Tregs), and subsequently elucidated and crystallized our understanding of them. Human Tregs have emerged as essential to immune tolerance and the prevention of autoimmune diseases and are typically contemporaneously characterized by their CD3+CD4+CD25high CD127lowFOXP3+ phenotype. It is important to note that FOXP3+ Tregs exhibit substantial diversity in their origin, phenotypic characteristics, and function. Identifying reliable markers is crucial to the accurate identification, quantification, and assessment of Tregs in health and disease, as well as the enrichment and expansion of viable cells for adoptive cell therapy. In our comprehensive review, we address the contributions of various markers identified in the last two decades since the master transcriptional factor FOXP3 was identified in establishing and enriching purity, lineage stability, tissue homing and suppressive proficiency in CD4+ Tregs. Additionally, our review delves into recent breakthroughs in innovative Treg-based therapies, underscoring the significance of distinct markers in their therapeutic utilization. Understanding Treg subsets holds the key to effectively harnessing human Tregs for immunotherapeutic approaches.
Collapse
Affiliation(s)
| | - Kayani Kayani
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Department of Academic Surgery, Queen Elizabeth Hospital, University of Birmingham, Birmingham, United Kingdom
- Department of Renal Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Mateusz Gliwiński
- Department of Medical Immunology, Medical University of Gdańsk, Gdańsk, Poland
| | - Yueyuan Hu
- Center for Regenerative Therapies Dresden, Technical University Dresden, Dresden, Germany
| | | | | | - Justyna Sakowska
- Department of Medical Immunology, Medical University of Gdańsk, Gdańsk, Poland
| | - Martyna Tomaszewicz
- Department of Medical Immunology, Medical University of Gdańsk, Gdańsk, Poland
| | | | - Kavitha Lakshmi
- Center for Regenerative Therapies Dresden, Technical University Dresden, Dresden, Germany
| | | | - Piotr Trzonkowski
- Department of Medical Immunology, Medical University of Gdańsk, Gdańsk, Poland
| | - Ye Htun Oo
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Birmingham Advanced Cellular Therapy Facility, University of Birmingham, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network - Rare Liver Centre, Birmingham, United Kingdom
| | - Anke Fuchs
- Center for Regenerative Therapies Dresden, Technical University Dresden, Dresden, Germany
| |
Collapse
|
|
13
|
Lin H, Xu Y, Lin C. Heterogeneity and subtypes of CD4 + regulatory T cells: implications for tumor therapy. Front Immunol 2024; 14:1291796. [PMID: 38250084 PMCID: PMC10796559 DOI: 10.3389/fimmu.2023.1291796] [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: 09/10/2023] [Accepted: 12/13/2023] [Indexed: 01/23/2024] Open
Abstract
In the conventional view, CD4+ regulatory T cell (Treg) represents a subset of lymphocytes that involve the perception and negative regulation of the immune response. CD4+Treg plays an important role in the maintenance of immune homeostasis and immune tolerance. However, recent studies have revealed that CD4+Treg do not suppress the immune response in some diseases, but promote inflammatory injury or inhibit tissue remodeling, suggesting the functional heterogeneity of CD4+Treg. Their involvement in tumor pathogenesis is more complex than previously understood. This article reviews the relevant research on the heterogeneity of CD4+Treg, subtype classification, and their relationship with tumor therapy.
Collapse
Affiliation(s)
- Hanqing Lin
- Department of Otolaryngology, Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- National Regional Medical Center, Fujian Medical University, Fuzhou, China
| | - Yuanteng Xu
- Department of Otolaryngology, Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- National Regional Medical Center, Fujian Medical University, Fuzhou, China
| | - Chang Lin
- Department of Otolaryngology, Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- National Regional Medical Center, Fujian Medical University, Fuzhou, China
| |
Collapse
|
|
14
|
Trujillo-Ochoa JL, Kazemian M, Afzali B. The role of transcription factors in shaping regulatory T cell identity. Nat Rev Immunol 2023; 23:842-856. [PMID: 37336954 PMCID: PMC10893967 DOI: 10.1038/s41577-023-00893-7] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2023] [Indexed: 06/21/2023]
Abstract
Forkhead box protein 3-expressing (FOXP3+) regulatory T cells (Treg cells) suppress conventional T cells and are essential for immunological tolerance. FOXP3, the master transcription factor of Treg cells, controls the expression of multiples genes to guide Treg cell differentiation and function. However, only a small fraction (<10%) of Treg cell-associated genes are directly bound by FOXP3, and FOXP3 alone is insufficient to fully specify the Treg cell programme, indicating a role for other accessory transcription factors operating upstream, downstream and/or concurrently with FOXP3 to direct Treg cell specification and specialized functions. Indeed, the heterogeneity of Treg cells can be at least partially attributed to differential expression of transcription factors that fine-tune their trafficking, survival and functional properties, some of which are niche-specific. In this Review, we discuss the emerging roles of accessory transcription factors in controlling Treg cell identity. We specifically focus on members of the basic helix-loop-helix family (AHR), basic leucine zipper family (BACH2, NFIL3 and BATF), CUT homeobox family (SATB1), zinc-finger domain family (BLIMP1, Ikaros and BCL-11B) and interferon regulatory factor family (IRF4), as well as lineage-defining transcription factors (T-bet, GATA3, RORγt and BCL-6). Understanding the imprinting of Treg cell identity and specialized function will be key to unravelling basic mechanisms of autoimmunity and identifying novel targets for drug development.
Collapse
Affiliation(s)
- Jorge L Trujillo-Ochoa
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA
| | - Majid Kazemian
- Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN, USA
| | - Behdad Afzali
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA.
| |
Collapse
|
|
15
|
Tang C, Hu W. The role of Th17 and Treg cells in normal pregnancy and unexplained recurrent spontaneous abortion (URSA): New insights into immune mechanisms. Placenta 2023; 142:18-26. [PMID: 37603948 DOI: 10.1016/j.placenta.2023.08.065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 08/08/2023] [Accepted: 08/12/2023] [Indexed: 08/23/2023]
Abstract
Recurrent spontaneous abortion (RSA) has various causes, including chromosomal abnormalities, a prethrombotic state, and abnormal uterine anatomical factors. However, in about 50% of cases, the cause remains unknown and is referred to as unexplained recurrent spontaneous abortion (URSA). The fetus is protected from rejection by the maternal system, acting as an allogeneic gene, and immune tolerance serves as a crucial mechanism. The Th17/Treg cell paradigm's emergence as a new subpopulation of CD4+ T cells, interacting with one another, plays an essential role in the immune microenvironment and the body's defense system. This Th17/Treg cell model helps to explain the pathology of recurrent miscarriage that could not be accounted for by the original immune mechanism based on the Th1/Th2 model. Furthermore, the plasticity of Th17 and Treg cells holds innovative significance in autoimmunity and abortion. This paper reviews the role of Th17/Treg cellular immune response in the maintaining normal pregnancy and understanding unexplained recurrent spontaneous abortion.
Collapse
Affiliation(s)
- Cen Tang
- Kunming Medical University, Kunming, Yunnan, 650000, China
| | - Wanqin Hu
- Kunming Medical University Second Affiliated Hospital, Obstetrics Department, Kunming, Yunnan, 650000, China.
| |
Collapse
|
|
16
|
Leon J, Chowdhary K, Zhang W, Ramirez RN, André I, Hur S, Mathis D, Benoist C. Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction. Cell Rep 2023; 42:113018. [PMID: 37605532 PMCID: PMC10565790 DOI: 10.1016/j.celrep.2023.113018] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 07/26/2023] [Accepted: 08/04/2023] [Indexed: 08/23/2023] Open
Abstract
Mutations of the transcription factor FoxP3 in patients with "IPEX" (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) disrupt regulatory T cells (Treg), causing an array of multiorgan autoimmunity. To understand the functional impact of mutations across FoxP3 domains, without genetic and environmental confounders, six human FOXP3 missense mutations are engineered into mice. Two classes of mutations emerge from combined immunologic and genomic analyses. A mutation in the DNA-binding domain shows the same lymphoproliferation and multiorgan infiltration as complete FoxP3 knockouts but delayed by months. Tregs expressing this mutant FoxP3 are destabilized by normal Tregs in heterozygous females compared with hemizygous males. Mutations in other domains affect chromatin opening differently, involving different cofactors and provoking more specific autoimmune pathology (dermatitis, colitis, diabetes), unmasked by immunological challenges or incrossing NOD autoimmune-susceptibility alleles. This work establishes that IPEX disease heterogeneity results from the actual mutations, combined with genetic and environmental perturbations, explaining then the intra-familial variation in IPEX.
Collapse
Affiliation(s)
- Juliette Leon
- Department of Immunology, Harvard Medical School, Boston, MA, USA; INSERM UMR 1163, University of Paris, Imagine Institute, Paris, France
| | | | - Wenxiang Zhang
- Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | | | - Isabelle André
- INSERM UMR 1163, University of Paris, Imagine Institute, Paris, France
| | - Sun Hur
- Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Diane Mathis
- Department of Immunology, Harvard Medical School, Boston, MA, USA
| | | |
Collapse
|
|
17
|
Chowdhary K, Benoist C. A variegated model of transcription factor function in the immune system. Trends Immunol 2023; 44:530-541. [PMID: 37258360 PMCID: PMC10332489 DOI: 10.1016/j.it.2023.05.001] [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: 02/28/2023] [Revised: 04/26/2023] [Accepted: 05/01/2023] [Indexed: 06/02/2023]
Abstract
Specific combinations of transcription factors (TFs) control the gene expression programs that underlie specialized immune responses. Previous models of TF function in immunocytes had restricted each TF to a single functional categorization [e.g., lineage-defining (LDTFs) vs. signal-dependent TFs (SDTFs)] within one cell type. Synthesizing recent results, we instead propose a variegated model of immunological TF function, whereby many TFs have flexible and different roles across distinct cell states, contributing to cell phenotypic diversity. We discuss evidence in support of this variegated model, describe contextual inputs that enable TF diversification, and look to the future to imagine warranted experimental and computational tools to build quantitative and predictive models of immunocyte gene regulatory networks.
Collapse
|
|
18
|
Dolsten GA, Pritykin Y. Genomic Analysis of Foxp3 Function in Regulatory T Cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 210:880-887. [PMID: 36947819 PMCID: PMC10037560 DOI: 10.4049/jimmunol.2200864] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 01/23/2023] [Indexed: 03/24/2023]
Abstract
Regulatory T (Treg) cells are critical for tolerance to self-antigens and for preventing autoimmunity. Foxp3 has been identified as a Treg cell lineage-defining transcription factor controlling Treg cell differentiation and function. In this article, we review the current mechanistic and systemic understanding of Foxp3 function enabled by experimental and computational advances in high-throughput genomics.
Collapse
Affiliation(s)
- Gabriel A Dolsten
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA
- Quantitative and Computational Biology Graduate Program, Princeton University, Princeton, NJ, USA
| | - Yuri Pritykin
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA
- Department of Computer Science, Princeton University, Princeton, NJ, USA
| |
Collapse
|
|
19
|
Dikiy S, Rudensky AY. Principles of regulatory T cell function. Immunity 2023; 56:240-255. [PMID: 36792571 DOI: 10.1016/j.immuni.2023.01.004] [Citation(s) in RCA: 140] [Impact Index Per Article: 70.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/06/2023] [Accepted: 01/09/2023] [Indexed: 02/16/2023]
Abstract
Regulatory T (Treg) cells represent a distinct lineage of cells of the adaptive immune system indispensable for forestalling fatal autoimmune and inflammatory pathologies. The role of Treg cells as principal guardians of the immune system can be attributed to their ability to restrain all currently recognized major types of inflammatory responses through modulating the activity of a wide range of cells of the innate and adaptive immune system. This broad purview over immunity and inflammation is afforded by the multiple modes of action Treg cells exert upon their diverse molecular and cellular targets. Beyond the suppression of autoimmunity for which they were originally recognized, Treg cells have been implicated in tissue maintenance, repair, and regeneration under physiologic and pathologic conditions. Herein, we discuss the current and emerging understanding of Treg cell effector mechanisms in the context of the basic properties of Treg cells that endow them with such functional versatility.
Collapse
Affiliation(s)
- Stanislav Dikiy
- Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, Ludwig Center at Memorial Sloan Kettering Cancer Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA.
| | - Alexander Y Rudensky
- Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, Ludwig Center at Memorial Sloan Kettering Cancer Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
| |
Collapse
|
|
20
|
Malviya V, Yshii L, Junius S, Garg AD, Humblet-Baron S, Schlenner SM. Regulatory T-cell stability and functional plasticity in health and disease. Immunol Cell Biol 2023; 101:112-129. [PMID: 36479949 DOI: 10.1111/imcb.12613] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 12/07/2022] [Accepted: 12/07/2022] [Indexed: 12/13/2022]
Abstract
FOXP3-expressing regulatory T cells (Treg ) are indispensable for immune homeostasis and tolerance, and in addition tissue-resident Treg have been found to perform noncanonical, tissue-specific functions. For optimal tolerogenic function during inflammatory disease, Treg are equipped with mechanisms that assure lineage stability. Treg lineage stability is closely linked to the installation and maintenance of a lineage-specific epigenetic landscape, specifically a Treg -specific DNA demethylation pattern. At the same time, for local and directed immune regulation Treg must possess a level of functional plasticity that requires them to partially acquire T helper cell (TH ) transcriptional programs-then referred to as TH -like Treg . Unleashing TH programs in Treg , however, is not without risk and may threaten the epigenetic stability of Treg with consequently pathogenic ex-Treg contributing to (auto-) inflammatory conditions. Here, we review how the Treg -stabilizing epigenetic landscape is installed and maintained, and further discuss the development, necessity and lineage instability risks of TH 1-, TH 2-, TH 17-like Treg and follicular Treg .
Collapse
Affiliation(s)
- Vanshika Malviya
- Department of Microbiology, Immunology and Transplantation, KU Leuven, University of Leuven, Leuven, Belgium
| | - Lidia Yshii
- Department of Neurosciences, KU Leuven, Leuven, Belgium
| | - Steffie Junius
- Department of Microbiology, Immunology and Transplantation, KU Leuven, University of Leuven, Leuven, Belgium
| | - Abhishek D Garg
- Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Stephanie Humblet-Baron
- Department of Microbiology, Immunology and Transplantation, KU Leuven, University of Leuven, Leuven, Belgium
| | - Susan M Schlenner
- Department of Microbiology, Immunology and Transplantation, KU Leuven, University of Leuven, Leuven, Belgium
| |
Collapse
|
|
21
|
Mazzieri A, Montanucci P, Basta G, Calafiore R. The role behind the scenes of Tregs and Th17s in Hashimoto's thyroiditis: Toward a pivotal role of FOXP3 and BACH2. Front Immunol 2022; 13:1098243. [PMID: 36578493 PMCID: PMC9791026 DOI: 10.3389/fimmu.2022.1098243] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
In Hashimoto's thyroiditis (HT), the genetic bases play a central role in determining development of the disease. In particular, the most frequent genes involved in the onset of HT are the Human Leukocyte Antigen (HLA). However, there are other genes and transcription factors in the autoimmune background of HT, both isolated and as part of autoimmune polyendocrine syndromes (APS). Recently more interest is being fueled toward BACH2 (BTB Domain and CNC Homolog 2), that promotes Tregs (T regulators lymphocytes) differentiation and enhances Treg-mediated immunity. The synergistic interaction between environmental agents and the aforementioned genes leads to the onset of autoimmunity and ultimately to damage of the thyroid gland. In this scenario, the role of Th17 (T helper-17 lymphocytes) and Treg cells is still less defined as compared to action of Th1 cells (T helper-1 lymphocytes) and cytotoxic lymphocytes (CD8 + T lymphocytes). Evidences show that an imbalance of Th17/Treg ratio represents a prognostic factor with respect to the gland damage. Moreover, the deficient ability of Treg to inhibit the proliferation of T cells against the self can break the immune balance. In light of these considerations, the use of genetic panels and the progress of immunotherapy could allow for better targeting treatment and preventive interventions in subjects with potential or early stage of HT.
Collapse
Affiliation(s)
- Alessio Mazzieri
- Translational Medicine and Surgery, Department of Medicine and Surgery, University of Perugia, Perugia, Italy,*Correspondence: Alessio Mazzieri,
| | - Pia Montanucci
- Division of Internal Medicine and Endocrine and Metabolic Sciences (MISEM), Laboratory for Endocrine Cell Transplants and Biohybrid Organs, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Giuseppe Basta
- Division of Internal Medicine and Endocrine and Metabolic Sciences (MISEM), Laboratory for Endocrine Cell Transplants and Biohybrid Organs, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Riccardo Calafiore
- Division of Internal Medicine and Endocrine and Metabolic Sciences (MISEM), Laboratory for Endocrine Cell Transplants and Biohybrid Organs, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| |
Collapse
|
|
22
|
Braband KL, Kaufmann T, Floess S, Zou M, Huehn J, Delacher M. Stepwise acquisition of unique epigenetic signatures during differentiation of tissue Treg cells. Front Immunol 2022; 13:1082055. [PMID: 36569861 PMCID: PMC9772052 DOI: 10.3389/fimmu.2022.1082055] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 11/18/2022] [Indexed: 12/12/2022] Open
Abstract
Regulatory T cells in non-lymphoid tissues are not only critical for maintaining self-tolerance, but are also important for promoting organ homeostasis and tissue repair. It is proposed that the generation of tissue Treg cells is a stepwise, multi-site process, accompanied by extensive epigenome remodeling, finally leading to the acquisition of unique tissue-specific epigenetic signatures. This process is initiated in the thymus, where Treg cells acquire core phenotypic and functional properties, followed by a priming step in secondary lymphoid organs that permits Treg cells to exit the lymphoid organs and seed into non-lymphoid tissues. There, a final specialization process takes place in response to unique microenvironmental cues in the respective tissue. In this review, we will summarize recent findings on this multi-site tissue Treg cell differentiation and highlight the importance of epigenetic remodeling during these stepwise events.
Collapse
Affiliation(s)
- Kathrin L. Braband
- Institute for Immunology, University Medical Center Mainz, Mainz, Germany,Research Center for Immunotherapy, University Medical Center Mainz, Mainz, Germany
| | - Tamara Kaufmann
- Institute for Immunology, University Medical Center Mainz, Mainz, Germany,Research Center for Immunotherapy, University Medical Center Mainz, Mainz, Germany
| | - Stefan Floess
- Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Mangge Zou
- Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Jochen Huehn
- Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany,Hannover Medical School, Hannover, Germany
| | - Michael Delacher
- Institute for Immunology, University Medical Center Mainz, Mainz, Germany,Research Center for Immunotherapy, University Medical Center Mainz, Mainz, Germany,*Correspondence: Michael Delacher,
| |
Collapse
|
|
23
|
Lichen Sclerosus: A Current Landscape of Autoimmune and Genetic Interplay. Diagnostics (Basel) 2022; 12:diagnostics12123070. [PMID: 36553077 PMCID: PMC9777366 DOI: 10.3390/diagnostics12123070] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 11/24/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022] Open
Abstract
Lichen sclerosus (LS) is an acquired chronic inflammatory dermatosis predominantly affecting the anogenital area with recalcitrant itching and soreness. Progressive or persistent LS may cause urinary and sexual disturbances and an increased risk of local skin malignancy with a prevalence of up to 11%. Investigations on lipoid proteinosis, an autosomal recessive genodermatosis caused by loss-of-function mutations in the extracellular matrix protein 1 (ECM1) gene, led to the discovery of a humoral autoimmune response to the identical molecule in LS, providing evidence for an autoimmune and genetic counterpart targeting ECM1. This paper provides an overview of the fundamental importance and current issue of better understanding the immunopathology attributed to ECM1 in LS. Furthermore, we highlight the pleiotropic action of ECM1 in homeostatic and structural maintenance of skin biology as well as in a variety of human disorders possibly associated with impaired or gained ECM1 function, including the inflammatory bowel disease ulcerative colitis, Th2 cell-dependent airway allergies, T-cell and B-cell activation, and the demyelinating central nervous system disease multiple sclerosis, to facilitate sharing the concept as a plausible therapeutic target of this attractive molecule.
Collapse
|
|
24
|
Schlöder J, Shahneh F, Schneider FJ, Wieschendorf B. Boosting regulatory T cell function for the treatment of autoimmune diseases – That’s only half the battle! Front Immunol 2022; 13:973813. [PMID: 36032121 PMCID: PMC9400058 DOI: 10.3389/fimmu.2022.973813] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 07/18/2022] [Indexed: 01/04/2023] Open
Abstract
Regulatory T cells (Treg) represent a subset of specialized T cells that are essential for the regulation of immune responses and maintenance of peripheral tolerance. Once activated, Treg exert powerful immunosuppressive properties, for example by inhibiting T cell-mediated immune responses against self-antigens, thereby protecting our body from autoimmunity. Autoimmune diseases such as multiple sclerosis, rheumatoid arthritis or systemic lupus erythematosus, exhibit an immunological imbalance mainly characterized by a reduced frequency and impaired function of Treg. In addition, there has been increasing evidence that – besides Treg dysfunction – immunoregulatory mechanisms fail to control autoreactive T cells due to a reduced responsiveness of T effector cells (Teff) for the suppressive properties of Treg, a process termed Treg resistance. In order to efficiently treat autoimmune diseases and thus fully induce immunological tolerance, a combined therapy aimed at both enhancing Treg function and restoring Teff responsiveness could most likely be beneficial. This review provides an overview of immunomodulating drugs that are currently used to treat various autoimmune diseases in the clinic and have been shown to increase Treg frequency as well as Teff sensitivity to Treg-mediated suppression. Furthermore, we discuss strategies on how to boost Treg activity and function, and their potential use in the treatment of autoimmunity. Finally, we present a humanized mouse model for the preclinical testing of Treg-activating substances in vivo.
Collapse
Affiliation(s)
- Janine Schlöder
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- ActiTrexx GmbH, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- *Correspondence: Janine Schlöder,
| | - Fatemeh Shahneh
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Franz-Joseph Schneider
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- ActiTrexx GmbH, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Björn Wieschendorf
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- ActiTrexx GmbH, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| |
Collapse
|
|
25
|
Chen W, Huang W, Xue Y, Chen Y, Qian W, Ma J, August A, Wang J, Zheng SG, Lin J. Neuropilin-1 Identifies a New Subpopulation of TGF-β-Induced Foxp3 + Regulatory T Cells With Potent Suppressive Function and Enhanced Stability During Inflammation. Front Immunol 2022; 13:900139. [PMID: 35603221 PMCID: PMC9114772 DOI: 10.3389/fimmu.2022.900139] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
CD4+Foxp3+ regulatory T cells (Tregs) play a crucial role in preventing autoimmunity and inflammation. There are naturally-derived in the thymus (tTreg), generated extrathymically in the periphery (pTreg), and induced in vitro culture (iTreg) with different characteristics of suppressiveness, stability, and plasticity. There is an abundance of published data on neuropilin-1 (Nrp-1) as a tTreg marker, but little data exist on iTreg. The fidelity of Nrp-1 as a tTreg marker and its role in iTreg remains to be explored. This study found that Nrp-1 was expressed by a subset of Foxp3+CD4+T cells in the central and peripheral lymphoid organs in intact mice, as well as in iTreg. Nrp-1+iTreg and Nrp-1-iTreg were adoptively transferred into a T cell-mediated colitis model to determine their ability to suppress inflammation. Differences in gene expression between Nrp-1+ and Nrp-1-iTreg were analyzed by RNA sequencing. We demonstrated that the Nrp-1+ subset of the iTreg exhibited enhanced suppressive function and stability compared to the Nrp-1- counterpart both in vivo and in vitro, partly depending on IL-10. We found that Nrp-1 is not an exclusive marker of tTreg, however, it is a biomarker identifying a new subset of iTreg with enhanced suppressive function, implicating a potential for Nrp-1+iTreg cell therapy for autoimmune and inflammatory diseases.
Collapse
Affiliation(s)
- Weiqian Chen
- Division of Rheumatology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Division of Rheumatology, Department of Medicine, Pennsylvania State University Hershey College of Medicine, Hershey, PA, United States
| | - Weishan Huang
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States.,Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, LA, United States
| | - Youqiu Xue
- Division of Rheumatology, Department of Medicine, Pennsylvania State University Hershey College of Medicine, Hershey, PA, United States.,Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ye Chen
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wenbin Qian
- Division of Hematology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jilin Ma
- Division of Rheumatology, Department of Medicine, Pennsylvania State University Hershey College of Medicine, Hershey, PA, United States
| | - Avery August
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, LA, United States
| | - Julie Wang
- Division of Rheumatology, Department of Medicine, Pennsylvania State University Hershey College of Medicine, Hershey, PA, United States.,Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Song Guo Zheng
- Division of Rheumatology, Department of Medicine, Pennsylvania State University Hershey College of Medicine, Hershey, PA, United States.,Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jin Lin
- Division of Rheumatology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
|
26
|
Krzyzanowska AK, Haynes Ii RAH, Kovalovsky D, Lin HC, Osorio L, Edelblum KL, Corcoran LM, Rabson AB, Denzin LK, Sant'Angelo DB. Zbtb20 identifies and controls a thymus-derived population of regulatory T cells that play a role in intestinal homeostasis. Sci Immunol 2022; 7:eabf3717. [PMID: 35522722 DOI: 10.1126/sciimmunol.abf3717] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The expression of BTB-ZF transcription factors such as ThPOK in CD4+ T cells, Bcl6 in T follicular helper cells, and PLZF in natural killer T cells defines the fundamental nature and characteristics of these cells. Screening for lineage-defining BTB-ZF genes led to the discovery of a subset of T cells that expressed Zbtb20. About half of Zbtb20+ T cells expressed FoxP3, the lineage-defining transcription factor for regulatory T cells (Tregs). Zbtb20+ Tregs were phenotypically and genetically distinct from the larger conventional Treg population. Zbtb20+ Tregs constitutively expressed mRNA for interleukin-10 and produced high levels of the cytokine upon primary activation. Zbtb20+ Tregs were enriched in the intestine and specifically expanded when inflammation was induced by the use of dextran sodium sulfate. Conditional deletion of Zbtb20 in T cells resulted in a loss of intestinal epithelial barrier integrity. Consequently, knockout (KO) mice were acutely sensitive to colitis and often died because of the disease. Adoptive transfer of Zbtb20+ Tregs protected the Zbtb20 conditional KO mice from severe colitis and death, whereas non-Zbtb20 Tregs did not. Zbtb20 was detected in CD24hi double-positive and CD62Llo CD4 single-positive thymocytes, suggesting that expression of the transcription factor and the phenotype of these cells were induced during thymic development. However, Zbtb20 expression was not induced in "conventional" Tregs by activation in vitro or in vivo. Thus, Zbtb20 expression identified and controlled the function of a distinct subset of Tregs that are involved in intestinal homeostasis.
Collapse
Affiliation(s)
- Agata K Krzyzanowska
- Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.,Rutgers Graduate School of Biomedical Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Rashade A H Haynes Ii
- Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Damian Kovalovsky
- Center for Cancer Research, National Cancer Institute National Institutes of Health, Bethesda, MD 20892, USA
| | - Hsin-Ching Lin
- Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Louis Osorio
- Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Karen L Edelblum
- Department of Pathology and Laboratory Medicine Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Lynn M Corcoran
- The Walter and Eliza Hall Institute of Medical Research Immunology Division, Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3052, Australia
| | - Arnold B Rabson
- Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.,Rutgers Graduate School of Biomedical Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.,Department of Pediatrics and Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Lisa K Denzin
- Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.,Rutgers Graduate School of Biomedical Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.,Department of Pediatrics and Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Derek B Sant'Angelo
- Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.,Rutgers Graduate School of Biomedical Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.,Department of Pediatrics and Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| |
Collapse
|
|
27
|
Jiang Z, Zhu H, Wang P, Que W, Zhong L, Li X, Du F. Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity. MedComm (Beijing) 2022; 3:e137. [PMID: 35474948 PMCID: PMC9023873 DOI: 10.1002/mco2.137] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 04/06/2022] [Accepted: 04/07/2022] [Indexed: 12/11/2022] Open
Abstract
CD4+CD25+ regulatory T cells (Tregs), a subpopulation of naturally CD4+ T cells that characteristically express transcription factor Forkhead box P3 (FOXP3), play a pivotal role in the maintenance of immune homeostasis and the prevention of autoimmunity. With the development of biological technology, the understanding of plasticity and stability of Tregs has been further developed. Recent studies have suggested that human Tregs are functionally and phenotypically diverse. The functions and mechanisms of different phenotypes of Tregs in different disease settings, such as tumor microenvironment, autoimmune diseases, and transplantation, have gradually become hot spots of immunology research that arouse extensive attention. Among the complex functions, CD4+CD25+FOXP3+ Tregs possess a potent immunosuppressive capacity and can produce various cytokines, such as IL‐2, IL‐10, and TGF‐β, to regulate immune homeostasis. They can alleviate the progression of diseases by resisting inflammatory immune responses, whereas promoting the poor prognosis of diseases by helping cells evade immune surveillance or suppressing effector T cells activity. Therefore, methods for targeting Tregs to regulate their functions in the immune microenvironment, such as depleting them to strengthen tumor immunity or expanding them to treat immunological diseases, need to be developed. Here, we discuss that different subpopulations of Tregs are essential for the development of immunotherapeutic strategies involving Tregs in human diseases.
Collapse
Affiliation(s)
- Zhongyi Jiang
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Haitao Zhu
- Department of Hepatobiliary Surgery The Affiliated Hospital of Guizhou Medical University Guizhou P. R. China
| | - Pusen Wang
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Weitao Que
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Lin Zhong
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Xiao‐Kang Li
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
- Division of Transplantation Immunology National Research Institute for Child Health and Development Tokyo Japan
| | - Futian Du
- Department of Hepatobiliary Surgery Weifang People's Hospital Shandong P. R. China
| |
Collapse
|
|
28
|
Burkhardt NB, Elleder D, Schusser B, Krchlíková V, Göbel TW, Härtle S, Kaspers B. The Discovery of Chicken Foxp3 Demands Redefinition of Avian Regulatory T Cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:1128-1138. [PMID: 35173035 DOI: 10.4049/jimmunol.2000301] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 12/17/2021] [Indexed: 11/19/2022]
Abstract
Since the publication of the first chicken genome sequence, we have encountered genes playing key roles in mammalian immunology, but being seemingly absent in birds. One of those was, until recently, Foxp3, the master transcription factor of regulatory T cells in mammals. Therefore, avian regulatory T cell research is still poorly standardized. In this study we identify a chicken ortholog of Foxp3 We prove sequence homology with known mammalian and sauropsid sequences, but also reveal differences in major domains. Expression profiling shows an association of Foxp3 and CD25 expression levels in CD4+CD25+ peripheral T cells and identifies a CD4-CD25+Foxp3high subset of thymic lymphocytes that likely represents yet undescribed avian regulatory T precursor cells. We conclude that Foxp3 is existent in chickens and that it shares certain functional characteristics with its mammalian ortholog. Nevertheless, pathways for regulatory T cell development and Foxp3 function are likely to differ between mammals and birds. The identification and characterization of chicken Foxp3 will help to define avian regulatory T cells and to analyze their functional properties and thereby advance the field of avian immunology.
Collapse
Affiliation(s)
- Nina B Burkhardt
- Department for Veterinary Sciences, Ludwig-Maximilians-Universität Munich, Munich, Germany
| | - Daniel Elleder
- Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic, Prague, Czech Republic; and
| | - Benjamin Schusser
- Reproductive Biotechnology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Veronika Krchlíková
- Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic, Prague, Czech Republic; and
| | - Thomas W Göbel
- Department for Veterinary Sciences, Ludwig-Maximilians-Universität Munich, Munich, Germany
| | - Sonja Härtle
- Department for Veterinary Sciences, Ludwig-Maximilians-Universität Munich, Munich, Germany
| | - Bernd Kaspers
- Department for Veterinary Sciences, Ludwig-Maximilians-Universität Munich, Munich, Germany;
| |
Collapse
|
|
29
|
Shaikh A, Olkhanud PB, Gangaplara A, Kone A, Patel S, Gucek M, Fitzhugh CD. Thrombospondin-1, Platelet Factor 4, and Galectin-1 are Associated with Engraftment in Patients with Sickle Cell Disease Who Underwent Haploidentical HSCT. Transplant Cell Ther 2022; 28:249.e1-249.e13. [PMID: 35131485 PMCID: PMC9176382 DOI: 10.1016/j.jtct.2022.01.027] [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: 12/30/2021] [Revised: 01/26/2022] [Accepted: 01/27/2022] [Indexed: 11/17/2022]
Abstract
Sickle cell disease (SCD) is an inherited red blood cell disorder that leads to significant morbidity and early mortality. The most widely available curative approach remains allogeneic hematopoietic stem cell transplantation (HSCT). HLA-haploidentical (haplo) HSCT expands the donor pool considerably and is a practical alternative for these patients, but traditionally with an increased risk of allograft rejection. Biomarkers in patient plasma could potentially help predict HSCT outcome and allow treatment at an early stage to reverse or prevent graft rejection. Reliable, noninvasive methods to predict engraftment or rejection early after HSCT are needed. We sought to detect variations in the plasma proteomes of patients who engrafted compared with those who rejected their grafts. We used a mass spectrometry-based proteomics approach to identify candidate biomarkers associated with engraftment and rejection by comparing plasma samples obtained from 9 engrafted patients and 10 patients who experienced graft rejection. A total of 1378 proteins were identified, 45 of which were differentially expressed in the engrafted group compared with the rejected group. Based on bioinformatics analysis results, information from the literature, and immunoassay availability, 7 proteins-thrombospondin-1 (Tsp-1), platelet factor 4 (Pf-4), talin-1, moesin, cell division control protein 42 homolog (CDC42), galectin-1 (Gal-1), and CD9-were selected for further analysis. We compared these protein concentrations among 35 plasma samples (engrafted, n = 9; rejected, n = 10; healthy volunteers, n = 8; nontransplanted SCD, n = 8). ELISA analysis confirmed the significant up-regulation of Tsp-1, Pf-4, and Gal-1 in plasma samples from engrafted patients compared with rejected patients, healthy African American volunteers, and the nontransplanted SCD group (P < .01). By receiver operating characteristic analysis, these 3 proteins distinguished engrafted patients from the other groups (area under the curve, >0.8; P < .05). We then evaluated the concentration of these 3 proteins in samples collected pre-HSCT and at days +30, +60, +100, and +180 post-HSCT. The results demonstrate that Tsp-1 and Pf-4 stratified engrafted patients as early as day 60 post-HSCT (P < .01), and that Gal-1 was significantly higher in engrafted patients as early as day 30 post-HSCT (P < .01). We also divided the rejected group into those who experienced primary (n = 5) and secondary graft rejection (n = 5) and found that engrafted patients had significantly higher Tsp-1 levels compared with patients who developed primary graft rejection at days +60 and +100 (P < .05), as well as higher Pf-4 levels compared with patients who developed primary graft rejection at post-transplantation (PT) day 100. Furthermore, Tsp-1 levels were significantly higher at PT days 60 and 100 and Pf-4 levels were higher at PT day 100 in engrafted patients compared with those who experienced secondary graft rejection. Increased concentrations of plasma Gal-1, Tsp-1, and Pf-4 could reflect increased T regulatory cells, IL-10, and TGF-β, which are essential players in the initiation of immunologic tolerance. These biomarkers may provide opportunities for preemptive intervention to minimize the incidence of graft rejection.
Collapse
Affiliation(s)
- Ahmad Shaikh
- Cellular and Molecular Therapeutics Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland; Department of Biology, The Catholic University of America, Washington, DC; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Kingdom of Saudi Arabia
| | - Purevdorj B Olkhanud
- Cellular and Molecular Therapeutics Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Arunakumar Gangaplara
- Cellular and Molecular Therapeutics Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Abdoul Kone
- Cellular and Molecular Therapeutics Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Sajni Patel
- Proteomics Core, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Marjan Gucek
- Proteomics Core, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Courtney D Fitzhugh
- Cellular and Molecular Therapeutics Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
| |
Collapse
|
|
30
|
Ramirez RN, Chowdhary K, Leon J, Mathis D, Benoist C. FoxP3 associates with enhancer-promoter loops to regulate T reg-specific gene expression. Sci Immunol 2022; 7:eabj9836. [PMID: 35030035 PMCID: PMC9059705 DOI: 10.1126/sciimmunol.abj9836] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Gene expression programs are specified by higher-order chromatin structure and enhancer-promoter loops (EPLs). T regulatory cell (Treg) identity is dominantly specified by the transcription factor (TF) FoxP3, whose mechanism of action is unclear. We applied chromatin conformation capture with immunoprecipitation (HiChIP) in Treg and closely related conventional CD4+ T cells (Tconv). EPLs identified by H3K27Ac HiChIP showed a range of connection intensity, with some superconnected genes. TF-specific HiChIP showed that FoxP3 interacts with EPLs at a large number of genes, including some not differentially expressed in Treg versus Tconv, but enriched at the core Treg signature loci that it up-regulates. FoxP3 association correlated with heightened H3K27Ac looping, as ascertained by analysis of FoxP3-deficient Treg-like cells. There was marked asymmetry in the loci where FoxP3 associated at the enhancer- or the promoter-side of EPLs, with enrichment for different transcriptional cofactors. FoxP3 EPL intensity distinguished gene clusters identified by single-cell ATAC-seq as covarying between individual Tregs, supporting a direct transactivation model for FoxP3 in determining Treg identity.
Collapse
Affiliation(s)
| | | | - Juliette Leon
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Diane Mathis
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | | |
Collapse
|
|
31
|
Boardman DA, Levings MK. Emerging strategies for treating autoimmune disorders with genetically modified Treg cells. J Allergy Clin Immunol 2022; 149:1-11. [PMID: 34998473 DOI: 10.1016/j.jaci.2021.11.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 11/12/2021] [Accepted: 11/16/2021] [Indexed: 12/17/2022]
Abstract
Gene editing of living cells is a cornerstone of present-day medical research that has enabled scientists to address fundamental biologic questions and identify novel strategies to treat diseases. The ability to manipulate adoptive cell therapy products has revolutionized cancer immunotherapy and promises similar results for the treatment of autoimmune diseases, inflammatory disorders, and transplant rejection. Clinical trials have recently deemed polyclonal regulatory T (Treg) cell therapy to be a safe therapeutic option, but questions remain regarding the efficacy of this approach. In this review, we discuss how gene editing technologies are being applied to transform the future of Treg cell therapy, focusing on the preclinical strategies that are currently being investigated to enhance the efficacy, function, and survival of human Treg cells. We explore approaches that may be used to generate immunoregulatory cells ex vivo, detail emerging strategies that are being used to modify these cells (such as using chimeric antigen receptors to confer antigen specificity), and outline concepts that have been explored to repurpose conventional T cells to target and destroy autoreactive and alloreactive lymphocytes. We also describe the key hurdles that currently hinder the clinical adoption of Treg cell therapy and propose potential future avenues of research for this field.
Collapse
Affiliation(s)
- Dominic A Boardman
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Megan K Levings
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.
| |
Collapse
|
|
32
|
DiToro D, Basu R. Emerging Complexity in CD4 +T Lineage Programming and Its Implications in Colorectal Cancer. Front Immunol 2021; 12:694833. [PMID: 34489941 PMCID: PMC8417887 DOI: 10.3389/fimmu.2021.694833] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 08/04/2021] [Indexed: 12/17/2022] Open
Abstract
The intestinal immune system has the difficult task of protecting a large environmentally exposed single layer of epithelium from pathogens without allowing inappropriate inflammatory responses. Unmitigated inflammation drives multiple pathologies, including the development of colorectal cancer. CD4+T cells mediate both the suppression and promotion of intestinal inflammation. They comprise an array of phenotypically and functionally distinct subsets tailored to a specific inflammatory context. This diversity of form and function is relevant to a broad array of pathologic and physiologic processes. The heterogeneity underlying both effector and regulatory T helper cell responses to colorectal cancer, and its impact on disease progression, is reviewed herein. Importantly, T cell responses are dynamic; they exhibit both quantitative and qualitative changes as the inflammatory context shifts. Recent evidence outlines the role of CD4+T cells in colorectal cancer responses and suggests possible mechanisms driving qualitative alterations in anti-cancer immune responses. The heterogeneity of T cells in colorectal cancer, as well as the manner and mechanism by which they change, offer an abundance of opportunities for more specific, and likely effective, interventional strategies.
Collapse
Affiliation(s)
- Daniel DiToro
- Brigham and Women's Hospital, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States.,Ragon Institute of MGH MIT and Harvard, Cambridge, MA, United States
| | - Rajatava Basu
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (UAB), Birmingham, AL, United States
| |
Collapse
|
|
33
|
Saxena V, Lakhan R, Iyyathurai J, Bromberg JS. Mechanisms of exTreg induction. Eur J Immunol 2021; 51:1956-1967. [PMID: 33975379 PMCID: PMC8338747 DOI: 10.1002/eji.202049123] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/19/2021] [Accepted: 05/10/2021] [Indexed: 12/18/2022]
Abstract
CD4+ CD25+ Foxp3+ Tregs play an important role in the maintenance of the immune system by regulating immune responses and resolving inflammation. Tregs exert their function by suppressing other immune cells and mediating peripheral self-tolerance. Under homeostatic conditions, Tregs are stable T-cell populations. However, under inflammatory environments, Tregs are converted to CD4+ CD25low Foxp3low cells. These cells are termed "exTreg" or "exFoxp3" cells. The molecular mechanism of Treg transition to exTregs remains incompletely understood. Uncertainties might be explained by a lack of consensus of biological markers to define Treg subsets in general and exTregs in particular. In this review, we summarize known markers of Tregs and factors responsible for exTreg generation including cytokines, signaling pathways, transcription factors, and epigenetic mechanisms. We also identify studies demonstrating the presence of exTregs in various diseases and sources of exTregs. Understanding the biology of Treg transition to exTregs will help in designing Treg-based therapeutic approaches.
Collapse
Affiliation(s)
- Vikas Saxena
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Ram Lakhan
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Jegan Iyyathurai
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Jonathan S. Bromberg
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| |
Collapse
|
|
34
|
Lee JK, Koo SY, Nam HM, Lee JB, Ko J, Kim KM, Park EJ, Kim TJ, Lee H, Go H, Lee CW. Ssu72 is a T-cell receptor-responsive modifier that is indispensable for regulatory T cells. Cell Mol Immunol 2021; 18:1395-1411. [PMID: 33850312 PMCID: PMC8166877 DOI: 10.1038/s41423-021-00671-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 03/03/2021] [Indexed: 12/11/2022] Open
Abstract
The homeostatic balance between effector T cells and regulatory T cells (Tregs) is crucial for adaptive immunity; however, epigenetic programs that inhibit phosphorylation to regulate Treg development, peripheral expression, and suppressive activity are elusive. Here, we found that the Ssu72 phosphatase is activated by various T-cell receptor signaling pathways, including the T-cell receptor and IL-2R pathways, and localizes at the cell membrane. Deletion of Ssu72 in T cells disrupts CD4+ T-cell differentiation into Tregs in the periphery via the production of high levels of the effector cytokines IL-2 and IFNγ, which induce CD4+ T-cell activation and differentiation into effector cell lineages. We also found a close correlation between downregulation of Ssu72 and severe defects in mucosal tolerance in patients. Interestingly, Ssu72 forms a complex with PLCγ1, which is an essential effector molecule for T-cell receptor signaling as well as Treg development and function. Ssu72 deficiency impairs PLCγ1 downstream signaling and results in failure of Foxp3 induction. Thus, our studies show that the Ssu72-mediated cytokine response coordinates the differentiation and function of Treg cells in the periphery.
Collapse
Affiliation(s)
- Jin-Kwan Lee
- Research Institute, Curogen Technology, Suwon, South Korea
| | - Seo-Young Koo
- Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, South Korea
| | - Hye-Mi Nam
- Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, South Korea
- MOGAM Institute for Biomedical Research, Gyeonggi, South Korea
| | - Jee-Boong Lee
- Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, South Korea
| | - Jiwon Ko
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Kyung-Mo Kim
- Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, South Korea
| | - Eun-Ji Park
- Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, South Korea
| | - Tae Jin Kim
- Department of Immunology, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Ho Lee
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center, Gyeonggi, South Korea.
| | - Heounjeong Go
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
| | - Chang-Woo Lee
- Research Institute, Curogen Technology, Suwon, South Korea.
- Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, South Korea.
| |
Collapse
|
|
35
|
Jiang Q, Yang G, Liu Q, Wang S, Cui D. Function and Role of Regulatory T Cells in Rheumatoid Arthritis. Front Immunol 2021; 12:626193. [PMID: 33868244 PMCID: PMC8047316 DOI: 10.3389/fimmu.2021.626193] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
Rheumatoid arthritis (RA) is a systemic and heterogeneous autoimmune disease with symmetrical polyarthritis as its critical clinical manifestation. The basic cause of autoimmune diseases is the loss of tolerance to self or harmless antigens. The loss or functional deficiency of key immune cells, regulatory T (Treg) cells, has been confirmed in human autoimmune diseases. The pathogenesis of RA is complex, and the dysfunction of Tregs is one of the proposed mechanisms underlying the breakdown of self-tolerance leading to the progression of RA. Treg cells are a vital component of peripheral immune tolerance, and the transcription factor Foxp3 plays a major immunosuppressive role. Clinical treatment for RA mainly utilizes drugs to alleviate the progression of disease and relieve disease activity, and the ideal treatment strategy should be to re-induce self-tolerance before obvious tissue injury. Treg cells are one of the ideal options. This review will introduce the classification, mechanism of action, and characteristics of Treg cells in RA, which provides insights into clinical RA treatment.
Collapse
Affiliation(s)
- Qi Jiang
- Department of Blood Transfusion, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Guocan Yang
- Department of Blood Transfusion, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Qi Liu
- Department of Blood Transfusion, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Shengjun Wang
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Dawei Cui
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
|
36
|
Single-cell analyses of Crohn's disease tissues reveal intestinal intraepithelial T cells heterogeneity and altered subset distributions. Nat Commun 2021; 12:1921. [PMID: 33771991 PMCID: PMC7997960 DOI: 10.1038/s41467-021-22164-6] [Citation(s) in RCA: 133] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 03/03/2021] [Indexed: 02/06/2023] Open
Abstract
Crohn's disease (CD) is a chronic transmural inflammation of intestinal segments caused by dysregulated interaction between microbiome and gut immune system. Here, we profile, via multiple single-cell technologies, T cells purified from the intestinal epithelium and lamina propria (LP) from terminal ileum resections of adult severe CD cases. We find that intraepithelial lymphocytes (IEL) contain several unique T cell subsets, including NKp30+γδT cells expressing RORγt and producing IL-26 upon NKp30 engagement. Further analyses comparing tissues from non-inflamed and inflamed regions of patients with CD versus healthy controls show increased activated TH17 but decreased CD8+T, γδT, TFH and Treg cells in inflamed tissues. Similar analyses of LP find increased CD8+, as well as reduced CD4+T cells with an elevated TH17 over Treg/TFH ratio. Our analyses of CD tissues thus suggest a potential link, pending additional validations, between transmural inflammation, reduced IEL γδT cells and altered spatial distribution of IEL and LP T cell subsets.
Collapse
|
|
37
|
Adamczyk A, Pastille E, Kehrmann J, Vu VP, Geffers R, Wasmer MH, Kasper S, Schuler M, Lange CM, Muggli B, Rau TT, Klein D, Hansen W, Krebs P, Buer J, Westendorf AM. GPR15 Facilitates Recruitment of Regulatory T Cells to Promote Colorectal Cancer. Cancer Res 2021; 81:2970-2982. [PMID: 33727229 DOI: 10.1158/0008-5472.can-20-2133] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 02/02/2021] [Accepted: 03/12/2021] [Indexed: 11/16/2022]
Abstract
Colorectal cancer is one of the most frequent malignancies worldwide. Despite considerable progress in early detection and treatment, there is still an unmet need for novel antitumor therapies, particularly in advanced colorectal cancer. Regulatory T cells (Treg) are increased in the peripheral blood and tumor tissue of patients with colorectal cancer. Recently, transient ablation of tumor-associated Tregs was shown to foster CD8+ T-cell-mediated antitumoral immunity in murine colorectal cancer models. However, before considering therapies on targeting Tregs in patients with cancer, detailed knowledge of the phenotype and features of tumor-associated Tregs is indispensable. Here, we demonstrate in a murine model of inflammation-induced colorectal cancer that tumor-associated Tregs are mainly of thymic origin and equipped with a specific set of molecules strongly associated with enhanced migratory properties. Particularly, a dense infiltration of Tregs in mouse and human colorectal cancer lesions correlated with increased expression of the orphan chemoattractant receptor GPR15 on these cells. Comprehensive gene expression analysis revealed that tumor-associated GPR15+ Tregs have a Th17-like phenotype, thereby producing IL17 and TNFα. Gpr15 deficiency repressed Treg infiltration in colorectal cancer, which paved the way for enhanced antitumoral CD8+ T-cell immunity and reduced tumorigenesis. In conclusion, GPR15 represents a promising novel target for modifying T-cell-mediated antitumoral immunity in colorectal cancer. SIGNIFICANCE: The G protein-coupled receptor 15, an unconventional chemokine receptor, directs Tregs into the colon, thereby modifying the tumor microenvironment and promoting intestinal tumorigenesis.See related commentary by Chakraborty and Zappasodi, p. 2817.
Collapse
Affiliation(s)
- Alexandra Adamczyk
- Infection Immunology, Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Eva Pastille
- Infection Immunology, Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jan Kehrmann
- Infection Immunology, Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Vivian P Vu
- Institute of Pathology, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Robert Geffers
- Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Marie-Hélène Wasmer
- Institute of Pathology, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Stefan Kasper
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Martin Schuler
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
| | - Christian M Lange
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Beat Muggli
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Tilman T Rau
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Diana Klein
- Institute for Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Wiebke Hansen
- Infection Immunology, Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Philippe Krebs
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Jan Buer
- Infection Immunology, Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Astrid M Westendorf
- Infection Immunology, Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
| |
Collapse
|
|
38
|
Li X, Zhang ZH, Zabed HM, Yun J, Zhang G, Qi X. An Insight into the Roles of Dietary Tryptophan and Its Metabolites in Intestinal Inflammation and Inflammatory Bowel Disease. Mol Nutr Food Res 2021; 65:e2000461. [PMID: 33216452 DOI: 10.1002/mnfr.202000461] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 10/14/2020] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel disease (IBD) is complex, chronic, and relapsing gastrointestinal inflammatory disorders, which includes mainly two conditions, namely ulcerative colitis (UC) and Crohn's disease (CD). Development of IBD in any individual is closely related to his/her autoimmune regulation, gene-microbiota interactions, and dietary factors. Dietary tryptophan (Trp) is an essential amino acid for intestinal mucosal cells, and it is associated with the intestinal inflammation, epithelial barrier, and energy homeostasis of the host. According to recent studies, Trp and its three major metabolic pathways, namely kynurenine (KYN) pathway, indole pathway, and 5-hydroxytryptamine (5-HT) pathway, have vital roles in the regulation of intestinal inflammation by acting directly or indirectly on the pro/anti-inflammatory cytokines, functions of various immune cells, as well as the intestinal microbial composition and homeostasis. In this review, recent advances in Trp- and its metabolites-associated intestinal inflammation are summarized. It further discusses the complex mechanisms and interrelationships of the three major metabolic pathways of Trp in regulating inflammation, which could elucidate the value of dietary Trp to be used as a nutrient for IBD patients.
Collapse
Affiliation(s)
- Xiaolan Li
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Zhi-Hong Zhang
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Hossain M Zabed
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Junhua Yun
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Guoyan Zhang
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Xianghui Qi
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| |
Collapse
|
|
39
|
Singh Y, Salker MS, Lang F. Green Tea Polyphenol-Sensitive Calcium Signaling in Immune T Cell Function. Front Nutr 2021; 7:616934. [PMID: 33585537 PMCID: PMC7876374 DOI: 10.3389/fnut.2020.616934] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 12/17/2020] [Indexed: 12/25/2022] Open
Abstract
Polyphenol compounds found in green tea have a great therapeutic potential to influence multiple human diseases including malignancy and inflammation. In this mini review, we describe effects of green tea and the most important component EGCG in malignancy and inflammation. We focus on cellular mechanisms involved in the modification of T cell function by green tea polyphenol EGCG. The case is made that EGCG downregulates calcium channel activity by influencing miRNAs regulating expression of the channel at the post-transcriptional level.
Collapse
Affiliation(s)
- Yogesh Singh
- Institute of Medical Genetics and Applied Genomics, Eberhard Karls University, Tübingen, Germany
| | | | - Florian Lang
- Institute of Vegetative and Clinical Physiology, Eberhard Karls University, Tübingen, Germany
| |
Collapse
|
|
40
|
Barzaghi F, Passerini L. IPEX Syndrome: Improved Knowledge of Immune Pathogenesis Empowers Diagnosis. Front Pediatr 2021; 9:612760. [PMID: 33692972 PMCID: PMC7937806 DOI: 10.3389/fped.2021.612760] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/21/2021] [Indexed: 12/18/2022] Open
Abstract
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic autoimmune disease with variable clinical manifestations, ranging from early-onset severe autoimmunity, including enteropathy, eczema, and type 1 diabetes, to late-onset or atypical symptoms. Despite the clinical heterogeneity, the unifying feature of IPEX is mutation of the FOXP3 gene, which encodes a transcription factor essential for maintenance of thymus-derived regulatory T cells (Tregs). In IPEX patients, Tregs can be present, although unstable and impaired in function, unable to inhibit proliferation and cytokine production of effector T (Teff) cells. Mutated FOXP3 can also disrupt other compartments: FOXP3-deficient Teff cells proliferate more than the wild-type counterpart, display altered T-cell-receptor signaling response, a reduced T-naïve compartment and a skew toward a Th2 profile. Due to FOXP3 mutations, the frequency of autoreactive B cells is increased and the IgA and IgE production is altered, together with early emergence of tissue-specific autoantibodies. Recently, the awareness of the wide clinical spectrum of IPEX improved the diagnostic tools. In cases presenting with enteropathy, histological evaluation is helpful, although there are no pathognomonic signs of disease. On the other hand, the study of FOXP3 expression and in vitro Treg function, as well as the detection of specific circulating autoantibodies, is recommended to narrow the differential diagnosis. Nowadays, Sanger sequencing should be limited to cases presenting with the classical triad of symptoms; otherwise, next-generation sequencing is recommended, given the cost-effectiveness and the advantage of excluding IPEX-like syndromes. The latter approach could be time spearing in children with severe phenotypes and candidate to advanced therapies.
Collapse
Affiliation(s)
- Federica Barzaghi
- Department of Paediatric Immunohematology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Laura Passerini
- Mechanisms of Peripheral Tolerance Unit, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
| |
Collapse
|
|
41
|
Regulatory T Cell Stability and Plasticity in Atherosclerosis. Cells 2020; 9:cells9122665. [PMID: 33322482 PMCID: PMC7764358 DOI: 10.3390/cells9122665] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/08/2020] [Accepted: 12/08/2020] [Indexed: 12/17/2022] Open
Abstract
Regulatory T cells (Tregs) express the lineage-defining transcription factor FoxP3 and play crucial roles in self-tolerance and immune homeostasis. Thymic tTregs are selected based on affinity for self-antigens and are stable under most conditions. Peripheral pTregs differentiate from conventional CD4 T cells under the influence of TGF-β and other cytokines and are less stable. Treg plasticity refers to their ability to inducibly express molecules characteristic of helper CD4 T cell lineages like T-helper (Th)1, Th2, Th17 or follicular helper T cells. Plastic Tregs retain FoxP3 and are thought to be specialized regulators for “their” lineage. Unstable Tregs lose FoxP3 and switch to become exTregs, which acquire pro-inflammatory T-helper cell programs. Atherosclerosis with systemic hyperlipidemia, hypercholesterolemia, inflammatory cytokines, and local hypoxia provides an environment that is likely conducive to Tregs switching to exTregs.
Collapse
|
|
42
|
Parobchak N, Rao S, Negron A, Schaefer J, Bhattacharya M, Radovick S, Babwah AV. Uterine Gpr83 mRNA is highly expressed during early pregnancy and GPR83 mediates the actions of PEN in endometrial and non-endometrial cells. F&S SCIENCE 2020; 1:67-77. [PMID: 35559741 DOI: 10.1016/j.xfss.2020.06.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 05/28/2020] [Accepted: 06/13/2020] [Indexed: 06/15/2023]
Abstract
OBJECTIVE To characterize the expression and signaling of uterine GPR83 in vivo in the nonpregnant and pregnant mouse and in vitro in human endometrial and nonendometrial cells. DESIGN Controlled laboratory study. SETTING Not applicable. PATIENTS Not applicable. INTERVENTIONS None. MAIN OUTCOME MEASURES Expression of uterine Gpr83 was determined by quantitative polymerase chain reaction throughout the estrous cycle and during early pregnancy in ovarian-stimulated and non-ovarian-stimulated mice and pregnant and pseudopregnant mice. Expression was also determined in ovariectomized mice after the administration of oil, E2, P4, or E2 + P4 and in stromal cells following 6 days of in vitro decidualization. GPR83 signaling was studied in human endometrial and embryonic kidney cell lines. Cells were treated by PEN, a GPR83 ligand, and PEN-induced extracellular signal-regulated kinase (ERK) phosphorylation was assayed under conditions that blocked Gαq/11 and/or β-arrestin signaling. RESULTS Uterine Gpr83 is expressed throughout the estrous cycle and during early pregnancy; expression increases dramatically at the time of uterine receptivity, embryo implantation, and stromal cell decidualization. In the ovariectomized mouse, hormone add-back reveals that Gpr83 expression is highly responsive to the combined treatment of E2 and P4, and studies in the ovarian-stimulated mouse show that expression is also very sensitive to changes in E2 and P4 and is therefore tightly regulated by E2 and P4. At the implantation site, expression is elevated up to D6 of pregnancy and then declines rapidly on D7 and D8, suggesting that if there is any involvement in decidualization, it is likely associated with primary but not secondary stromal cell decidualization. This premise was supported by the observation that stromal cell decidualization in vitro progresses with a decline in Gpr83 expression. In ERα/PR-expressing endometrial Ishikawa cells, GPR83 mediates PEN signals in a Gαq/11-dependent manner, and studies conducted in HEK 293 cells lacking β-arrestin revealed that GPR83 also signals via a β-arrestin-dependent manner. When signaling by either one or both pathways is downregulated, cells exhibit a major reduction in responsiveness to PEN treatment, demonstrating that signaling by both pathways is significant. CONCLUSION We hypothesize that PEN/GPR83 signaling regulates uterine receptivity, embryo implantation, and primary stromal cell decidualization by coupling to Gαq/11- and β-arrestin-dependent pathways.
Collapse
Affiliation(s)
- Nataliya Parobchak
- Laboratory of Human Growth and Reproductive Development, Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; School of Graduate Studies, Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Shivani Rao
- Laboratory of Human Growth and Reproductive Development, Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
| | - Ariel Negron
- Laboratory of Human Growth and Reproductive Development, Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
| | - Jennifer Schaefer
- Laboratory of Human Growth and Reproductive Development, Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; School of Graduate Studies, Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Moshmi Bhattacharya
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; Child Health Institute of New Jersey, New Brunswick, New Jersey
| | - Sally Radovick
- Laboratory of Human Growth and Reproductive Development, Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; School of Graduate Studies, Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Child Health Institute of New Jersey, New Brunswick, New Jersey
| | - Andy V Babwah
- Laboratory of Human Growth and Reproductive Development, Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; School of Graduate Studies, Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Child Health Institute of New Jersey, New Brunswick, New Jersey.
| |
Collapse
|
|
43
|
Ng MSF, Roth TL, Mendoza VF, Marson A, Burt TD. Helios enhances the preferential differentiation of human fetal CD4 + naïve T cells into regulatory T cells. Sci Immunol 2020; 4:4/41/eaav5947. [PMID: 31757834 DOI: 10.1126/sciimmunol.aav5947] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 10/24/2019] [Indexed: 12/14/2022]
Abstract
T cell receptor (TCR) stimulation and cytokine cues drive the differentiation of CD4+ naïve T cells into effector T cell populations with distinct proinflammatory or regulatory functions. Unlike adult naïve T cells, human fetal naïve CD4+ T cells preferentially differentiate into FOXP3+ regulatory T (Treg) cells upon TCR activation independent of exogenous cytokine signaling. This cell-intrinsic predisposition for Treg differentiation is implicated in the generation of tolerance in utero; however, the underlying mechanisms remain largely unknown. Here, we identify epigenetic and transcriptional programs shared between fetal naïve T and committed Treg cells that are inactive in adult naïve T cells and show that fetal-derived induced Treg (iTreg) cells retain this transcriptional program. We show that a subset of Treg-specific enhancers is accessible in fetal naïve T cells, including two active superenhancers at Helios Helios is expressed in fetal naïve T cells but not in adult naïve T cells, and fetal iTreg cells maintain Helios expression. CRISPR-Cas9 ablation of Helios in fetal naïve T cells impaired their differentiation into iTreg cells upon TCR stimulation, reduced expression of immunosuppressive genes in fetal iTreg cells such as IL10, and increased expression of proinflammatory genes including IFNG Consequently, Helios knockout fetal iTreg cells had reduced IL-10 and increased IFN-γ cytokine production. Together, our results reveal important roles for Helios in enhancing preferential fetal Treg differentiation and fine-tuning eventual Treg function. The Treg-biased programs identified within fetal naïve T cells could potentially be used to engineer enhanced iTreg populations for adoptive cellular therapies.
Collapse
Affiliation(s)
- Melissa S F Ng
- Biomedical Sciences Graduate Program, University of California, San Francisco (UCSF), San Francisco, CA 94143, USA.,Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Singapore 138648, Singapore
| | - Theodore L Roth
- Biomedical Sciences Graduate Program, University of California, San Francisco (UCSF), San Francisco, CA 94143, USA.,Department of Microbiology and Immunology, UCSF, San Francisco, CA 94143, USA.,Diabetes Center, UCSF, San Francisco, CA 94143, USA
| | - Ventura F Mendoza
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, CA 94143, USA
| | - Alexander Marson
- Department of Microbiology and Immunology, UCSF, San Francisco, CA 94143, USA.,Diabetes Center, UCSF, San Francisco, CA 94143, USA.,Innovative Genomics Institute, University of California, Berkeley, CA 94720, USA.,Department of Medicine, UCSF, San Francisco, CA 94143, USA.,Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.,UCSF Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA 94158, USA.,Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA
| | - Trevor D Burt
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, CA 94143, USA. .,Department of Pediatrics, Division of Neonatology, UCSF, San Francisco, CA 94110, USA
| |
Collapse
|
|
44
|
Ohkura N, Sakaguchi S. Transcriptional and epigenetic basis of Treg cell development and function: its genetic anomalies or variations in autoimmune diseases. Cell Res 2020; 30:465-474. [PMID: 32367041 PMCID: PMC7264322 DOI: 10.1038/s41422-020-0324-7] [Citation(s) in RCA: 209] [Impact Index Per Article: 41.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 04/08/2020] [Indexed: 01/01/2023] Open
Abstract
Naturally arising regulatory CD4+ T (Treg) cells, which specifically express the transcription factor FoxP3 in the nucleus and CD25 and CTLA-4 on the cell surface, are a T-cell subpopulation specialized for immune suppression, playing a key role in maintaining immunological self-tolerance and homeostasis. FoxP3 is required for Treg function, especially for its suppressive activity. However, FoxP3 expression per se is not necessary for Treg cell lineage commitment in the thymus and insufficient for full Treg-type gene expression in mature Treg cells. It is Treg-specific epigenetic changes such as CpG demethylation and histone modification that can confer a stable and heritable pattern of Treg type gene expression on developing Treg cells in a FoxP3-independent manner. Anomalies in the formation of Treg-specific epigenome, in particular, Treg-specific super-enhancers, which largely include Treg-specific DNA demethylated regions, are indeed able to cause autoimmune diseases in rodents. Furthermore, in humans, single nucleotide polymorphisms in Treg-specific DNA demethylated regions associated with Treg signature genes, such as IL2RA (CD25) and CTLA4, can affect the development and function of naïve Treg cells rather than effector T cells. Such genetic variations are therefore causative of polygenic common autoimmune diseases including type 1 diabetes and rheumatoid arthritis via affecting endogenous natural Treg cells. These findings on the transcription factor network with FoxP3 at a key position as well as Treg-specific epigenetic landscape facilitate our understanding of Treg cell development and function, and can be exploited to prepare functionally stable FoxP3-expressing Treg cells from antigen-specific conventional T cells to treat autoimmune diseases.
Collapse
Affiliation(s)
- Naganari Ohkura
- Experimental immunology, Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Shimon Sakaguchi
- Experimental immunology, Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| |
Collapse
|
|
45
|
Ansa-Addo EA, Huang HC, Riesenberg B, Iamsawat S, Borucki D, Nelson MH, Nam JH, Chung D, Paulos CM, Liu B, Yu XZ, Philpott C, Howe PH, Li Z. RNA binding protein PCBP1 is an intracellular immune checkpoint for shaping T cell responses in cancer immunity. SCIENCE ADVANCES 2020; 6:eaaz3865. [PMID: 32523987 PMCID: PMC7259945 DOI: 10.1126/sciadv.aaz3865] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 03/25/2020] [Indexed: 05/11/2023]
Abstract
Distinct lineages of T cells can act in response to various environmental cues to either drive or restrict immune-mediated pathology. Here, we identify the RNA binding protein, poly(C)-binding protein 1 (PCBP1) as an intracellular immune checkpoint that is up-regulated in activated T cells to prevent conversion of effector T (Teff) cells into regulatory T (Treg) cells, by restricting the expression of Teff cell-intrinsic Treg commitment programs. This was critical for stabilizing Teff cell functions and subverting immune-suppressive signals. T cell-specific deletion of Pcbp1 favored Treg cell differentiation, enlisted multiple inhibitory immune checkpoint molecules including PD-1, TIGIT, and VISTA on tumor-infiltrating lymphocytes, and blunted antitumor immunity. Our results demonstrate a critical role for PCBP1 as an intracellular immune checkpoint for maintaining Teff cell functions in cancer immunity.
Collapse
Affiliation(s)
- Ephraim A. Ansa-Addo
- Department of Microbiology and Immunology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
- Pelotonia Institute for Immuno-Oncology and Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center-James, Columbus, OH 43210, USA
| | - Huai-Cheng Huang
- Department of Microbiology and Immunology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
- National Taiwan University College of Medicine, Graduate Institute of Clinical Medicine, No.7 Chung San South Road, Taipei City 10002, Taiwan
| | - Brian Riesenberg
- Department of Microbiology and Immunology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
- Pelotonia Institute for Immuno-Oncology and Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center-James, Columbus, OH 43210, USA
| | - Supinya Iamsawat
- Department of Microbiology and Immunology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Davis Borucki
- Department of Microbiology and Immunology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Michelle H. Nelson
- Department of Microbiology and Immunology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Jin Hyun Nam
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Dongjun Chung
- Pelotonia Institute for Immuno-Oncology and Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center-James, Columbus, OH 43210, USA
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Chrystal M. Paulos
- Department of Microbiology and Immunology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Bei Liu
- Department of Microbiology and Immunology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Xue-Zhong Yu
- Department of Microbiology and Immunology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Caroline Philpott
- Genetics and Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, MD 20892, USA
| | - Philip H. Howe
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Zihai Li
- Department of Microbiology and Immunology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
- Pelotonia Institute for Immuno-Oncology and Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center-James, Columbus, OH 43210, USA
| |
Collapse
|
|
46
|
Zhang X, Olsen N, Zheng SG. The progress and prospect of regulatory T cells in autoimmune diseases. J Autoimmun 2020; 111:102461. [PMID: 32305296 DOI: 10.1016/j.jaut.2020.102461] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 04/08/2020] [Indexed: 12/16/2022]
Abstract
Regulatory T cells (Treg) are an important immune cell population, playing a crucial role in regulating immune tolerance and preventing autoimmune diseases. These cells consist of various cell sub-populations and generally have an immunoregulatory or suppressive role against immune responses. They also have a different cell heterogeneity and each populations has own biological characteristics. Treg deficiency, reduction, instability, reduced vitality and dysfunction all account for multiple autoimmune diseases. In this review, we have systemically reviewed Treg classification, phenotypic features, regulation of Foxp3 expression, plasticity and stability of Treg as well as their relationship with several important autoimmune diseases. We particularly focus on why and how inflammatory and diet environments affect the functional capacity and underlying mechanisms of Treg cell populations. We also summarize new advances in technologies which help to analyze and dissect these cells in molecular levels in-depth. We also clarify the possible clinical relevance on application of these cells in patients with autoimmune diseases. The advantages and weaknesses have been carefully discussed as well. We also propose the possible approaches to overcome these weaknesses of Treg cells in complicate environments. Thus, we have displayed the updated knowledge of Treg cells, which provides an overall insight into the role and mechanisms of Treg cells in autoimmune diseases.
Collapse
Affiliation(s)
- Ximei Zhang
- Institute of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China; Division of Rheumatology and Immunology, Department of Internal Medicine, Ohio State University College of Medicine, Columbus, PA, 43201, USA
| | - Nancy Olsen
- Division of Rheumatology, Department of Medicine at Penn State College of Medicine and Milton S. Hershey Medical Center, Hershey, 17033, USA
| | - Song Guo Zheng
- Division of Rheumatology and Immunology, Department of Internal Medicine, Ohio State University College of Medicine, Columbus, PA, 43201, USA.
| |
Collapse
|
|
47
|
Atif M, Conti F, Gorochov G, Oo YH, Miyara M. Regulatory T cells in solid organ transplantation. Clin Transl Immunology 2020; 9:e01099. [PMID: 32104579 PMCID: PMC7036337 DOI: 10.1002/cti2.1099] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 12/02/2019] [Accepted: 12/04/2019] [Indexed: 12/19/2022] Open
Abstract
The induction of graft tolerance remains the holy grail of transplantation. This is important as chronic allograft dysfunction and the side effects of immunosuppression regimens place a major burden on the lives of transplant patients and their healthcare systems. This has mandated the need to understand the immunobiology of graft rejection and identify novel therapeutics. Regulatory T (Treg) cells play an important role in modulating pro-inflammatory microenvironments and maintaining tissue homeostasis. However, there are fundamental unanswered questions regarding Treg cell immunobiology. These cells are a heterogeneous entity with functionally diverse roles. Moreover, the adoption of novel deeper immunophenotyping and genomic sequencing technologies has identified this phenotype and function to be more complex than expected. Hence, a comprehensive understanding of Treg cell heterogeneity is needed to safely and effectively exploit their therapeutic potential. From a clinical perspective, the recent decade has seen different clinical teams commence and complete first-in-man clinical trials utilising Treg cells as an adoptive cellular therapy. In this review, we discuss these trials from a translational perspective with an important focus on safety. Finally, we identify crucial knowledge gaps for future study.
Collapse
Affiliation(s)
- Muhammad Atif
- Sorbonne UniversitéInserm U1135Centre d'Immunologie et des Maladies Infectieuses (CIMI‐Paris)Hôpital Pitié‐SalpêtrièreAP‐HPParisFrance
- Unité de Transplantation HépatiqueHôpital Pitié‐SalpêtrièreAP‐HPParisFrance
- Centre for Liver and Gastro ResearchNIHR Birmingham Biomedical Research CentreUniversity of BirminghamBirminghamUK
- Academic Department of SurgeryUniversity of BirminghamBirminghamUK
| | - Filomena Conti
- Unité de Transplantation HépatiqueHôpital Pitié‐SalpêtrièreAP‐HPParisFrance
| | - Guy Gorochov
- Sorbonne UniversitéInserm U1135Centre d'Immunologie et des Maladies Infectieuses (CIMI‐Paris)Hôpital Pitié‐SalpêtrièreAP‐HPParisFrance
| | - Ye Htun Oo
- Centre for Liver and Gastro ResearchNIHR Birmingham Biomedical Research CentreUniversity of BirminghamBirminghamUK
- Liver Transplant and HPB UnitQueen Elizabeth HospitalUniversity Hospital Birmingham NHS Foundation TrustBirminghamUK
| | - Makoto Miyara
- Sorbonne UniversitéInserm U1135Centre d'Immunologie et des Maladies Infectieuses (CIMI‐Paris)Hôpital Pitié‐SalpêtrièreAP‐HPParisFrance
| |
Collapse
|
|
48
|
Wang X, Ni L, Wan S, Zhao X, Ding X, Dejean A, Dong C. Febrile Temperature Critically Controls the Differentiation and Pathogenicity of T Helper 17 Cells. Immunity 2020; 52:328-341.e5. [PMID: 32049050 DOI: 10.1016/j.immuni.2020.01.006] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 10/02/2019] [Accepted: 01/19/2020] [Indexed: 02/06/2023]
Abstract
Fever, an evolutionarily conserved physiological response to infection, is also commonly associated with many autoimmune diseases, but its role in T cell differentiation and autoimmunity remains largely unclear. T helper 17 (Th17) cells are critical in host defense and autoinflammatory diseases, with distinct phenotypes and pathogenicity. Here, we show that febrile temperature selectively regulated Th17 cell differentiation in vitro in enhancing interleukin-17 (IL-17), IL-17F, and IL-22 expression. Th17 cells generated under febrile temperature (38.5°C-39.5°C), compared with those under 37°C, showed enhanced pathogenic gene expression with increased pro-inflammatory activities in vivo. Mechanistically, febrile temperature promoted SUMOylation of SMAD4 transcription factor to facilitate its nuclear localization; SMAD4 deficiency selectively abrogated the effects of febrile temperature on Th17 cell differentiation both in vitro and ameliorated an autoimmune disease model. Our results thus demonstrate a critical role of fever in shaping adaptive immune responses with implications in autoimmune diseases.
Collapse
Affiliation(s)
- Xiaohu Wang
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, China.
| | - Lu Ni
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Siyuan Wan
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Xiaohong Zhao
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Xiao Ding
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Anne Dejean
- Nuclear Organization and Oncogenesis Laboratory, Department of Cell Biology and Infection, INSERM U993, Institute Pasteur, Paris 75015, France
| | - Chen Dong
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, China; Beijing Key Lab for Immunological Research on Chronic Diseases, Beijing 100084, China.
| |
Collapse
|
|
49
|
Colamatteo A, Carbone F, Bruzzaniti S, Galgani M, Fusco C, Maniscalco GT, Di Rella F, de Candia P, De Rosa V. Molecular Mechanisms Controlling Foxp3 Expression in Health and Autoimmunity: From Epigenetic to Post-translational Regulation. Front Immunol 2020; 10:3136. [PMID: 32117202 PMCID: PMC7008726 DOI: 10.3389/fimmu.2019.03136] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 12/23/2019] [Indexed: 12/12/2022] Open
Abstract
The discovery of the transcription factor Forkhead box-p3 (Foxp3) has shed fundamental insights into the understanding of the molecular determinants leading to generation and maintenance of T regulatory (Treg) cells, a cell population with a key immunoregulatory role. Work over the past few years has shown that fine-tuned transcriptional and epigenetic events are required to ensure stable expression of Foxp3 in Treg cells. The equilibrium between phenotypic plasticity and stability of Treg cells is controlled at the molecular level by networks of transcription factors that bind regulatory sequences, such as enhancers and promoters, to regulate Foxp3 expression. Recent reports have suggested that specific modifications of DNA and histones are required for the establishment of the chromatin structure in conventional CD4+ T (Tconv) cells for their future differentiation into the Treg cell lineage. In this review, we discuss the molecular events that control Foxp3 gene expression and address the associated alterations observed in human diseases. Also, we explore how Foxp3 influences the gene expression programs in Treg cells and how unique properties of Treg cell subsets are defined by other transcription factors.
Collapse
Affiliation(s)
- Alessandra Colamatteo
- Treg Cell Laboratory, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy
| | - Fortunata Carbone
- Laboratorio di Immunologia, Istituto per L'Endocrinologia e L'Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche (IEOS-CNR), Naples, Italy.,Unità di NeuroImmunologia, Fondazione Santa Lucia, Rome, Italy
| | - Sara Bruzzaniti
- Laboratorio di Immunologia, Istituto per L'Endocrinologia e L'Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche (IEOS-CNR), Naples, Italy.,Dipartimento di Biologia, Università degli Studi di Napoli "Federico II", Naples, Italy
| | - Mario Galgani
- Treg Cell Laboratory, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.,Laboratorio di Immunologia, Istituto per L'Endocrinologia e L'Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche (IEOS-CNR), Naples, Italy
| | - Clorinda Fusco
- Treg Cell Laboratory, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy
| | - Giorgia Teresa Maniscalco
- Dipartimento di Neurologia, Centro Regionale Sclerosi Multipla, Azienda Ospedaliera "A. Cardarelli", Naples, Italy
| | - Francesca Di Rella
- Clinical and Experimental Senology, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples, Italy
| | | | - Veronica De Rosa
- Laboratorio di Immunologia, Istituto per L'Endocrinologia e L'Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche (IEOS-CNR), Naples, Italy.,Unità di NeuroImmunologia, Fondazione Santa Lucia, Rome, Italy
| |
Collapse
|
|
50
|
Wang YX, Gu ZW, Cao ZW. Difference between CD25 +Tregs and Helios +Tregs in a murine model of allergic rhinitis. Braz J Otorhinolaryngol 2020; 87:550-556. [PMID: 31974056 PMCID: PMC9422529 DOI: 10.1016/j.bjorl.2019.12.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 06/20/2019] [Accepted: 12/09/2019] [Indexed: 01/09/2023] Open
Abstract
Introduction Regulatory T or Treg cells, balance the peripheral immune response to allergens in allergic rhinitis. Traditionally, Treg (CD25+ Treg) is identified by the coexpression of Foxp3 and CD25, but this strategy does not represent the true inhibitory function of Treg cells. Helios has been thought of as novel marker of activated Tregs, with an important inhibitory function. Consequently, Helios was proposed as a marker of Treg. Recent articles have shown that Foxp3 and Helios co-expression (Helios+Tregs) is an important functional stage of Treg. Objective To compare the prevalence of CD25+Tregs and Helios+Tregs using a mouse model of allergic rhinitis. Methods Twenty mice were randomized into two groups. The test group comprised 10 allergic rhinitis model mice exposed to ovalbumin; the control group was exposed to saline. The fractions of CD25+Tregs, Helios+Tregs, Helios+CD25+, and Helios+Foxp3+CD25+Tregs present in the two groups were determined using flow cytometry. Results CD25+Tregs and Helios+Tregs were less abundant in the spleen and nasal mucosa cells of the allergic rhinitis model compared with the control. We also observed fewer Helios+Tregs than CD25+Tregs in nasal mucosa and splenic cells of both control and test groups. Moreover, we observed fewer Helios+Foxp3+, Helios+CD25+, and Helios+Foxp3+CD25+ Tregs in the nasal mucosa in the allergic rhinitis model. Helios was expressed the most in CD4+ CD25+Foxp3+ T-cells, followed by CD4+ CD25−Foxp3− T-cells. Approximately 75% of CD25+Tregs were Helios+ in spleens of allergic rhinitis and control mice. Conclusion This is the first report of the proportions of Helios+Tregs in nasal mucosa and spleens of allergic rhinitis mice. Gating true inhibitory Tregs with the coexpression of Foxp3 and Helios might be more useful than relying on the expression of CD25. This study provides a new insight for Treg studies of allergic rhinitis, and the potential utility of the marker as a therapeutic target.
Collapse
Affiliation(s)
- Yun-Xiu Wang
- Shengjing Hospital of China Medical University, Department of Medical Insurance, Shenyang, Liaoning, China
| | - Zhao-Wei Gu
- Shengjing Hospital of China Medical University, Department of Otolaryngology Head and Neck Surgery, Shenyang, Liaoning, China.
| | - Zhi-Wei Cao
- Shengjing Hospital of China Medical University, Department of Otolaryngology Head and Neck Surgery, Shenyang, Liaoning, China
| |
Collapse
|