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Liu S, Zhang X, Wang W, Li X, Sun X, Zhao Y, Wang Q, Li Y, Hu F, Ren H. Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer. Mol Cancer 2024; 23:261. [PMID: 39574178 PMCID: PMC11580516 DOI: 10.1186/s12943-024-02165-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 10/31/2024] [Indexed: 11/25/2024] Open
Abstract
Metabolic alterations, a hallmark of cancer, enable tumor cells to adapt to their environment by modulating glucose, lipid, and amino acid metabolism, which fuels rapid growth and contributes to treatment resistance. In primary breast cancer, metabolic shifts such as the Warburg effect and enhanced lipid synthesis are closely linked to chemotherapy failure. Similarly, metastatic lesions often display distinct metabolic profiles that not only sustain tumor growth but also confer resistance to targeted therapies and immunotherapies. The review emphasizes two major aspects: the mechanisms driving metabolic resistance in both primary and metastatic breast cancer, and how the unique metabolic environments in metastatic sites further complicate treatment. By targeting distinct metabolic vulnerabilities at both the primary and metastatic stages, new strategies could improve the efficacy of existing therapies and provide better outcomes for breast cancer patients.
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Affiliation(s)
- Shan Liu
- Department of oncological surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xingda Zhang
- Department of oncological surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Wenzheng Wang
- Department of oncological surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xue Li
- Department of oncological surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xue Sun
- Department of oncological surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yuqian Zhao
- Department of oncological surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Qi Wang
- Department of oncological surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yingpu Li
- Department of oncological surgery, Harbin Medical University Cancer Hospital, Harbin, China.
| | - Fangjie Hu
- Department of Gastroenterology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
| | - He Ren
- Department of oncological surgery, Harbin Medical University Cancer Hospital, Harbin, China.
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Oparaugo NC, Ouyang K, Nguyen NPN, Nelson AM, Agak GW. Human Regulatory T Cells: Understanding the Role of Tregs in Select Autoimmune Skin Diseases and Post-Transplant Nonmelanoma Skin Cancers. Int J Mol Sci 2023; 24:1527. [PMID: 36675037 PMCID: PMC9864298 DOI: 10.3390/ijms24021527] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/04/2023] [Accepted: 01/09/2023] [Indexed: 01/15/2023] Open
Abstract
Regulatory T cells (Tregs) play an important role in maintaining immune tolerance and homeostasis by modulating how the immune system is activated. Several studies have documented the critical role of Tregs in suppressing the functions of effector T cells and antigen-presenting cells. Under certain conditions, Tregs can lose their suppressive capability, leading to a compromised immune system. For example, mutations in the Treg transcription factor, Forkhead box P3 (FOXP3), can drive the development of autoimmune diseases in multiple organs within the body. Furthermore, mutations leading to a reduction in the numbers of Tregs or a change in their function facilitate autoimmunity, whereas an overabundance can inhibit anti-tumor and anti-pathogen immunity. This review discusses the characteristics of Tregs and their mechanism of action in select autoimmune skin diseases, transplantation, and skin cancer. We also examine the potential of Tregs-based cellular therapies in autoimmunity.
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Affiliation(s)
- Nicole Chizara Oparaugo
- David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
- Division of Dermatology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Kelsey Ouyang
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
| | | | - Amanda M. Nelson
- Department of Dermatology, Penn State University College of Medicine, Hershey, PA 17033, USA
| | - George W. Agak
- Division of Dermatology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
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Ghosh S, Moorthy B, Haribabu B, Jala VR. Cytochrome P450 1A1 is essential for the microbial metabolite, Urolithin A-mediated protection against colitis. Front Immunol 2022; 13:1004603. [PMID: 36159798 PMCID: PMC9493474 DOI: 10.3389/fimmu.2022.1004603] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 08/19/2022] [Indexed: 12/02/2022] Open
Abstract
Background Cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1) pathway, which is regulated by aryl hydrocarbon receptor (AhR) plays an important role in chemical carcinogenesis and xenobiotic metabolism. Recently, we demonstrated that the microbial metabolite Urolithin A (UroA) mitigates colitis through its gut barrier protective and anti-inflammatory activities in an AhR-dependent manner. Here, we explored role of CYP1A1 in UroA-mediated gut barrier and immune functions in regulation of inflammatory bowel disease (IBD). Methods To determine the role of CYP1A1 in UroA-mediated protectives activities against colitis, we subjected C57BL/6 mice and Cyp1a1-/- mice to dextran sodium sulphate (DSS)-induced acute colitis model. The phenotypes of the mice were characterized by determining loss of body weight, intestinal permeability, systemic and colonic inflammation. Further, we evaluated the impact of UroA on regulation of immune cell populations by flow cytometry and confocal imaging using both in vivo and ex vivo model systems. Results UroA treatment mitigated DSS-induced acute colitis in the wildtype mice. However, UroA-failed to protect Cyp1a1-/- mice against colitis, as evident from non-recovery of body weight loss, shortened colon lengths and colon weight/length ratios. Further, UroA failed to reduce DSS-induced inflammation, intestinal permeability and upregulate tight junction proteins in Cyp1a1-/- mice. Interestingly, UroA induced the expansion of T-reg cells in a CYP1A1-dependent manner both in vivo and ex vivo models. Conclusion Our results suggest that CYP1A1 expression is essential for UroA-mediated enhanced gut barrier functions and protective activities against colitis. We postulate that CYP1A1 plays critical and yet unknown functions beyond xenobiotic metabolism in the regulation of gut epithelial integrity and immune systems to maintain gut homeostasis in IBD pathogenesis.
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Affiliation(s)
- Sweta Ghosh
- Department of Microbiology and Immunology, Brown Cancer Center, Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville, Louisville, KY, United States
| | - Bhagavatula Moorthy
- Department of Pediatrics and Neonatology, Baylor College of Medicine, Houston, TX, United States
| | - Bodduluri Haribabu
- Department of Microbiology and Immunology, Brown Cancer Center, Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville, Louisville, KY, United States
| | - Venkatakrishna Rao Jala
- Department of Microbiology and Immunology, Brown Cancer Center, Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville, Louisville, KY, United States
- *Correspondence: Venkatakrishna Rao Jala,
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Rogers D, Sood A, Wang H, van Beek JJP, Rademaker TJ, Artusa P, Schneider C, Shen C, Wong DC, Bhagrath A, Lebel MÈ, Condotta SA, Richer MJ, Martins AJ, Tsang JS, Barreiro LB, François P, Langlais D, Melichar HJ, Textor J, Mandl JN. Pre-existing chromatin accessibility and gene expression differences among naive CD4 + T cells influence effector potential. Cell Rep 2021; 37:110064. [PMID: 34852223 DOI: 10.1016/j.celrep.2021.110064] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 09/26/2021] [Accepted: 11/05/2021] [Indexed: 12/13/2022] Open
Abstract
CD4+ T cells have a remarkable potential to differentiate into diverse effector lineages following activation. Here, we probe the heterogeneity present among naive CD4+ T cells before encountering their cognate antigen to ask whether their effector potential is modulated by pre-existing transcriptional and chromatin landscape differences. Single-cell RNA sequencing shows that key drivers of variability are genes involved in T cell receptor (TCR) signaling. Using CD5 expression as a readout of the strength of tonic TCR interactions with self-peptide MHC, and sorting on the ends of this self-reactivity spectrum, we find that pre-existing transcriptional differences among naive CD4+ T cells impact follicular helper T (TFH) cell versus non-TFH effector lineage choice. Moreover, our data implicate TCR signal strength during thymic development in establishing differences in naive CD4+ T cell chromatin landscapes that ultimately shape their effector potential.
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Affiliation(s)
- Dakota Rogers
- Department of Physiology, McGill University, Montreal, QC, Canada; McGill University Research Centre on Complex Traits, Montreal, QC, Canada
| | - Aditi Sood
- Immunology-Oncology Unit, Maisonneuve-Rosemont Hospital Research Center, Montreal, QC, Canada; Department of Microbiology, Immunology, and Infectious Disease, Université de Montréal, Montreal, QC, Canada
| | - HanChen Wang
- Department of Physiology, McGill University, Montreal, QC, Canada; McGill University Research Centre on Complex Traits, Montreal, QC, Canada
| | - Jasper J P van Beek
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands
| | | | - Patricio Artusa
- Department of Physiology, McGill University, Montreal, QC, Canada; McGill University Research Centre on Complex Traits, Montreal, QC, Canada
| | - Caitlin Schneider
- McGill University Research Centre on Complex Traits, Montreal, QC, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Connie Shen
- McGill University Research Centre on Complex Traits, Montreal, QC, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Dylan C Wong
- McGill University Research Centre on Complex Traits, Montreal, QC, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Aanya Bhagrath
- Department of Physiology, McGill University, Montreal, QC, Canada; McGill University Research Centre on Complex Traits, Montreal, QC, Canada
| | - Marie-Ève Lebel
- Immunology-Oncology Unit, Maisonneuve-Rosemont Hospital Research Center, Montreal, QC, Canada
| | - Stephanie A Condotta
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Martin J Richer
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Andrew J Martins
- Multiscale Systems Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - John S Tsang
- Multiscale Systems Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Luis B Barreiro
- Department of Medicine, Genetic Section, University of Chicago, Chicago, IL, USA
| | - Paul François
- Department of Physics, McGill University, Montreal, QC, Canada
| | - David Langlais
- McGill University Research Centre on Complex Traits, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada; McGill University Genome Centre, Montreal, QC, Canada
| | - Heather J Melichar
- Immunology-Oncology Unit, Maisonneuve-Rosemont Hospital Research Center, Montreal, QC, Canada; Department of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Johannes Textor
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands
| | - Judith N Mandl
- Department of Physiology, McGill University, Montreal, QC, Canada; McGill University Research Centre on Complex Traits, Montreal, QC, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
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Autologous culture model of nodal B-cell lymphoma identifies ex vivo determinants of response to bispecific antibodies. Blood Adv 2021; 5:5060-5071. [PMID: 34587238 PMCID: PMC9153026 DOI: 10.1182/bloodadvances.2021005400] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/04/2021] [Indexed: 11/22/2022] Open
Abstract
High Helios but low ICOS expression in lymph node–derived regulatory T cells associates with ex vivo failure of BsAbs. Lenalidomide, nivolumab, and atezolizumab improve ex vivo response to BsAbs by potentiating T-cell effector functions. Bispecific antibodies (BsAbs) can induce long-term responses in patients with refractory and relapsed B-cell lymphoma. Nevertheless, response rates across patients are heterogeneous, and the factors determining quality and duration of responses are poorly understood. To identify key determinants of response to BsAbs, we established a primary, autologous culture model allowing us to mimic treatment with CD3xCD19 and CD3xCD20 BsAbs within the lymph node microenvironment ex vivo. T cell–mediated killing of lymphoma cells and proliferation of T cells varied significantly among patients but highly correlated between BsAbs targeting CD20 or CD19. Ex vivo response to BsAbs was significantly associated with expansion of T cells and secretion of effector molecules (eg, granzyme B, perforin) but not with expression of T-cell exhaustion (eg, PD1, TIM3) or activation markers (eg, CD25, CD69) or formation of intercellular contacts. In addition, we identified a distinct phenotype of regulatory T cells that was linked to ex vivo response independently from T-cell frequency at baseline. High expression levels of Aiolos (IKZF1), ICOS, and CXCR5 were positively associated with ex vivo response, whereas strong expression of Helios (IKZF2) had an unfavorable impact on ex vivo response to BsAbs. We further showed that lenalidomide, nivolumab, and atezolizumab improved ex vivo response to BsAbs by potentiating T-cell effector functions. In summary, our ex vivo study identified a distinct regulatory T-cell phenotype as a potential contributor to treatment failure of BsAbs and suggests drug combinations of high clinical relevance that could improve the efficacy of BsAbs.
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Negi S, Saini S, Tandel N, Sahu K, Mishra RP, Tyagi RK. Translating Treg Therapy for Inflammatory Bowel Disease in Humanized Mice. Cells 2021; 10:1847. [PMID: 34440615 PMCID: PMC8393385 DOI: 10.3390/cells10081847] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 02/07/2023] Open
Abstract
Crohn's disease and ulcerative colitis, two major forms of inflammatory bowel disease (IBD) in humans, afflicted in genetically predisposed individuals due to dysregulated immune response directed against constituents of gut flora. The defective immune responses mounted against the regulatory mechanisms amplify and maintain the IBD-induced mucosal inflammation. Therefore, restoring the balance between inflammatory and anti-inflammatory immunepathways in the gut may contribute to halting the IBD-associated tissue-damaging immune response. Phenotypic and functional characterization of various immune-suppressive T cells (regulatory T cells; Tregs) over the last decade has been used to optimize the procedures for in vitro expansion of these cells for developing therapeutic interventional strategies. In this paper, we review the mechanisms of action and functional importance of Tregs during the pathogenesis of IBD and modulating the disease induced inflammation as well as role of mouse models including humanized mice repopulated with the human immune system (HIS) to study the IBD. "Humanized" mouse models provide new tools to analyze human Treg ontogeny, immunobiology, and therapy and the role of Tregs in developing interventional strategies against IBD. Overall, humanized mouse models replicate the human conditions and prove a viable tool to study molecular functions of human Tregs to harness their therapeutic potential.
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MESH Headings
- Adoptive Transfer
- Animals
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/metabolism
- Colitis, Ulcerative/therapy
- Crohn Disease/genetics
- Crohn Disease/immunology
- Crohn Disease/metabolism
- Crohn Disease/therapy
- Disease Models, Animal
- Hematopoietic Stem Cell Transplantation
- Humans
- Mice, Transgenic
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/transplantation
- Transplantation, Heterologous
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Affiliation(s)
- Sushmita Negi
- Biomedical Parasitology and Nano-Immunology Lab, Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India; (S.N.); (S.S.); (K.S.)
- BERPDC Department, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India
| | - Sheetal Saini
- Biomedical Parasitology and Nano-Immunology Lab, Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India; (S.N.); (S.S.); (K.S.)
| | - Nikunj Tandel
- Institute of Science, Nirma University, Ahmedabad, Gujarat 382481, India;
| | - Kiran Sahu
- Biomedical Parasitology and Nano-Immunology Lab, Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India; (S.N.); (S.S.); (K.S.)
| | - Ravi P.N. Mishra
- BERPDC Department, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India
| | - Rajeev K. Tyagi
- Biomedical Parasitology and Nano-Immunology Lab, Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India; (S.N.); (S.S.); (K.S.)
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Regulatory T Cells and Inflammatory Mediators in Autoimmune Disease. J Invest Dermatol 2021; 142:774-780. [PMID: 34284898 DOI: 10.1016/j.jid.2021.05.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/10/2021] [Accepted: 05/17/2021] [Indexed: 12/22/2022]
Abstract
Regulatory T cells (Tregs) play a critical role in regulating tissue inflammation. Reduced Treg numbers and/or suppressive function contribute to autoimmune disease. Tregs can adopt the transcriptional programming of T helper (Th) type-1/2/17 cells to optimally suppress these subsets. Under specific conditions, these Th-like Tregs lose suppressive capacity and release proinflammatory cytokines to promote inflammation. This Treg plasticity depends on inflammatory mediators in the local environment. In this study, we review how cytokines impact Treg function and may contribute to autoimmune disease. A comprehensive understanding of Th-like Tregs may elucidate novel and more focused therapeutic approaches.
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Increased frequency of regulatory T cells in pediatric inflammatory bowel disease at diagnosis: a compensative role? Pediatr Res 2020; 87:853-861. [PMID: 31715619 DOI: 10.1038/s41390-019-0662-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 07/26/2019] [Accepted: 09/09/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis. We investigated two main types of Tregs, the CD4+FOXP3+ and IL-10+ Tr1, in pediatric subjects with inflammatory bowel disease (IBD) both at diagnosis and after the clinical remission. METHODS Peripheral blood Tregs were analyzed in 16 children with Crohn's disease (CD), 19 with ulcerative colitis (UC), and 14 healthy controls (HC). Two cocktails of fluoresceinated antibodies were used to discriminate between CD4+FOXP3+ and Tr1. RESULTS We observed in both CD and UC groups a higher frequency of Tr1 at diagnosis compared to controls, which decreased at follow-up compared to diagnosis, in particular in UC. Similarly, in UC patients the percentage of CD4+FOXP3+ Tregs markedly decreased at follow-up compared to the same patients at diagnosis and compared to HC. The expression of CTLA-4 in CD4+FOXP3+ Tregs increased in both groups at clinical remission. CONCLUSION This study shows that IBD children present at diagnosis an increased frequency of circulating Tregs, probably as a compensative reaction to tissue inflammation. During the clinical remission, the Treg frequency diminishes, and concomitantly, their activation status increases. Notwithstanding, the high Treg density at diagnosis is not sufficient to counteract the inflammation in the childhood IBD.
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Chyuan IT, Hsu PN. TRAIL regulates T cell activation and suppresses inflammation in autoimmune diseases. Cell Mol Immunol 2020; 17:1281-1283. [PMID: 32210394 DOI: 10.1038/s41423-020-0410-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 03/03/2020] [Indexed: 12/15/2022] Open
Affiliation(s)
- I-Tsu Chyuan
- Department of Internal Medicine, Cathay General Hospital, Taipei, China.,School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, China
| | - Ping-Ning Hsu
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, China. .,Department of Internal Medicine, National Taiwan University Hospital, Taipei, China.
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Ramani S, Chauhan N, Khatri V, Vitali C, Kalyanasundaram R. Wuchereria bancrofti macrophage migration inhibitory factor-2 (rWbaMIF-2) ameliorates experimental colitis. Parasite Immunol 2020; 42:e12698. [PMID: 31976564 DOI: 10.1111/pim.12698] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 01/13/2020] [Accepted: 01/14/2020] [Indexed: 12/20/2022]
Abstract
Immunomodulatory molecules produced by helminth parasites are receiving much attention recently as novel therapeutic agents for inflammation and autoimmune diseases. In this study, we show that macrophage migration inhibitory factor (MIF) homologue from the filarial parasite, Wuchereria bancrofti (rWbaMIF-2), can suppress inflammation in a dextran sulphate sodium salt (DSS)-induced colitis model. The disease activity index (DAI) in DSS given mice showed loss of body weight and bloody diarrhoea. At autopsy, colon of these mice showed severe inflammation and reduced length. Administration of rWbaMIF-2 significantly reduced the DAI in DSS-induced colitis mice. rWbaMIF-2-treated mice had no blood in the stools, and their colon length was similar to the normal colon with minimal inflammation and histological changes. Pro-inflammatory cytokine genes (TNF-α, IL-6, IFN-γ, IL-1β, IL-17A and NOS2) were downregulated in the colon tissue and peritoneal macrophages of rWbaMIF-2-treated mice. However, there were significant increases in IL-10-producing Treg and B1 cells in the colon and peritoneal cavity of rWbaMIF-2-treated mice. These findings suggested that rWbaMIF-2 treatment significantly ameliorated the clinical symptoms, inflammation and colon pathology in DSS given mice. This immunomodulatory effect of rWbaMIF-2 appeared to be by promoting the infiltration of Treg cells into the colon.
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Affiliation(s)
- Shriram Ramani
- Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, IL, USA
| | - Nikhil Chauhan
- Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, IL, USA
| | - Vishal Khatri
- Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, IL, USA
| | - Connie Vitali
- Department of Health Sciences Education, University of Illinois College of Medicine, Rockford, IL, USA
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TRAIL suppresses gut inflammation and inhibits colitogeic T-cell activation in experimental colitis via an apoptosis-independent pathway. Mucosal Immunol 2019; 12:980-989. [PMID: 31076664 PMCID: PMC7746525 DOI: 10.1038/s41385-019-0168-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 04/04/2019] [Accepted: 04/18/2019] [Indexed: 02/07/2023]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals. Recently, accumulating evidence demonstrated that TRAIL regulates autoimmune inflammation and immune cell homeostasis in several autoimmune animal models, suggesting a novel immunoregulatory role of TRAIL in autoimmune diseases. However, the impact of TRAIL in inflammatory bowel disease is yet undefined. This study is to address the therapeutic effects and immunoregulatory role of TRAIL in autoimmune gut inflammation. We demonstrated herein that TRAIL significantly suppressed gut inflammation and reduced the severity of colitis in a dextran sodium sulfate (DSS)-induced colitis model. Suppression of gut inflammation was not due to induction of apoptosis in colonic T cells, dendritic cells, or epithelium cells by TRAIL. In contrast, TRAIL directly inhibited activation of colitogenic T cells and development of gut inflammation in an adoptive transfer-induced colitis model. The anti-inflammatory effects of TRAIL on colitis were abolished when T cells from TRAIL receptor (TRAIL-R) knockout mice were adoptively transferred, suggesting that TRAIL regulates autoreactive colitogenic T-cell activation in the development of gut inflammation. Our results demonstrate that TRAIL effectively inhibited colonic T-cell activation and suppressed autoimmune colitis, suggesting a potential therapeutic application of TRAIL in human inflammatory bowel disease.
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12
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Su L, Jiang Y, Xu Y, Li X, Gao W, Xu C, Zeng C, Song J, Weng W, Liang W. Xihuang pill promotes apoptosis of Treg cells in the tumor microenvironment in 4T1 mouse breast cancer by upregulating MEKK1/SEK1/JNK1/AP-1 pathway. Biomed Pharmacother 2018; 102:1111-1119. [PMID: 29710529 DOI: 10.1016/j.biopha.2018.03.063] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 03/09/2018] [Accepted: 03/11/2018] [Indexed: 01/14/2023] Open
Abstract
OBJECTIVE To determine the role of the MEKK1/SEK1/JNK1/AP-1 pathway in the action of Xihuang pill (XHP) in reducing regulatory T (Treg) cell numbers in the tumor microenvironment in a 4T1 mouse breast cancer model, and to clarify the anti-tumor mechanism of XHP in breast cancer. METHODS We established a mouse 4T1 breast cancer model. Model mice were administered XHP for 2 weeks, and tumor tissues were then removed, weighed, sliced, and homogenized. Treg cells in the tumor microenvironment were isolated by magnetic cell sorting and analyzed by immunohistochemistry and flow cytometry. Treg cell apoptosis was detected by TdT-mediated dUTP nick end labeling. mRNA expression levels of MEKK1, SEK1, JNK1, and AP-1 in Treg cells in the tumor microenvironment were detected by quantitative real-time PCR and their protein expression levels were detected by immunofluorescence staining and western blot. RESULTS Tumor weights were significantly lower in the XHP groups compared with the untreated control group. The overall number of Treg cells in the tumor microenvironment decreased while the number of apoptotic Treg cells increased with increasing doses of XHP. mRNA and protein expression levels of MEKK1, SEK1, JNK1, and AP-1 in Treg cells in the tumor microenvironment increased with increasing doses of XHP. CONCLUSION XHP might promote Treg cell apoptosis in the tumor microenvironment and further inhibit the tumor growth of 4T1 mouse breast cancer. The mechanism of XHP may be related to upregulation of gene and protein expression of MEKK1, SEK1, JNK1, and AP-1 in Treg cells in the tumor microenvironment.
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Affiliation(s)
- Liang Su
- Xin Hua Affiliated Hospital of Dalian University, Dalian 116000, China
| | - Yiming Jiang
- Xin Hua Affiliated Hospital of Dalian University, Dalian 116000, China
| | - Yu Xu
- Medical College of Dalian University, Dalian 116622, China
| | - Xinye Li
- Medical College of Dalian University, Dalian 116622, China
| | - Wenbin Gao
- Department of Medical Oncology, The 3rd Affiliated Hospital of Shenzhen University, Shenzhen 518001, China
| | - Chunwei Xu
- Department of Pathology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
| | - Changqian Zeng
- Medical College of Dalian University, Dalian 116622, China
| | - Jie Song
- Medical College of Dalian University, Dalian 116622, China
| | - Wencai Weng
- Xin Hua Affiliated Hospital of Dalian University, Dalian 116000, China
| | - Wenbo Liang
- Medical College of Dalian University, Dalian 116622, China.
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Mohammed HA, Saboor-Yaraghi AA, Vahedi H, Yekaninejad MS, Panahi G, Hemmasi G, Lakzaei M, Mirshafiey A. Immunomodulatory effects of M2000 (β-D-Mannuronic acid) on TNF-α, IL-17 and FOXP3 gene expression in patients with inflammatory bowel disease. Int Immunopharmacol 2017; 51:107-113. [PMID: 28822915 DOI: 10.1016/j.intimp.2017.08.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 08/05/2017] [Accepted: 08/14/2017] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Inflammatory bowel diseases (IBD) are immune-mediated disorders that result from an aberrant immunological response to the gut luminal antigen in genetically susceptible patients. IBD is categorized into two serotype, Crohn's diseases (CD) and ulcerative colitis (UC), both subtype are important cause of gastrointestinal diseases. The increasing rate of hospitalization, with the high economic burden experienced by the IBD patients, calls for more concerted research efforts to design a potent and affordable treatment option for the treatment of IBD. AIMS/OBJECTIVE This research was designed to test the efficacy and potency of β-D Mannuronic acid (M2000) and assess if it could serve as a better therapeutic option in the treatment of IBD. METHODOLOGY Ten (10)ml of blood was aseptically collected into an EDTA container, from 24 IBD patients and 24 normal healthy controls. PBMC was isolated and stimulated with 1μg/ml of LPS in cell culture plate and incubated for 4h. The cells were later treated with 10μg/ml and 50μg/ml of β-D Mannuronic acid (M2000) and incubated for 24h at 37°C under 5% CO2 and 100% humidity. The RNA extractions, cDNA synthesis, and QRT-PCR were performed. RESULTS Our findings showed a significant down-regulation of TNF-α and IL-17 gene expression, while the expression of FOXP3 gene was significantly up-regulated. CONCLUSION This result has indicated that β-D Mannuronic acid (M2000) have immunoregulatory and anti-inflammatory effects on these cytokines that are pivotal in the pathogenesis of IBD.
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Affiliation(s)
- Hussaini Alhassan Mohammed
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, International Campus, TUMS-, IC, Tehran, Iran; Department of Immunology, Faculty of Medical Laboratory Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria
| | - Ali Akbar Saboor-Yaraghi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, International Campus, TUMS-, IC, Tehran, Iran
| | - Homayoun Vahedi
- Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mir Saeed Yekaninejad
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Ghodratollah Panahi
- Department of Medical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Gholamreza Hemmasi
- Department of Internal Medicine and Gastroenterology, Iran University of Medical Sciences, Tehran, Iran
| | - Mostafa Lakzaei
- Department of Medical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Mirshafiey
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, International Campus, TUMS-, IC, Tehran, Iran.
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Hu S, Chen M, Wang Y, Wang Z, Pei Y, Fan R, Liu X, Wang L, Zhou J, Zheng S, Zhang T, Lin Y, Zhang M, Tao R, Zhong J. mTOR Inhibition Attenuates Dextran Sulfate Sodium-Induced Colitis by Suppressing T Cell Proliferation and Balancing TH1/TH17/Treg Profile. PLoS One 2016; 11:e0154564. [PMID: 27128484 PMCID: PMC4851424 DOI: 10.1371/journal.pone.0154564] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 04/17/2016] [Indexed: 02/07/2023] Open
Abstract
It has been established that mammalian target of Rapamycin (mTOR) inhibitors have anti-inflammatory effects in models of experimental colitis. However, the underlying mechanism is largely unknown. In this research, we investigate the anti-inflammatory effects of AZD8055, a potent mTOR inhibitor, on T cell response in dextran sulfate sodium (DSS)-induced colitis in mice, a commonly used animal model of inflammatory bowel diseases (IBD). Severity of colitis is evaluated by changing of body weight, bloody stool, fecal consistency, histology evaluation and cytokine expression. We find that AZD8055 treatment attenuates DSS-induced body weight loss, colon length shortening and pathological damage of the colon. And AZD8055 treatment decreases colonic expression of genes encoding the pro-inflammatory cytokines interferon-γ, interleukin (IL)-17A, IL-1β,IL-6 and tumor necrosis factor(TNF)-a and increases colonic expression of anti-inflammatory cytokines IL-10. We show that AZD8055 treatment decreases the percentages of CD4+ T cells and CD8+ T cells in spleen, lymph nodes and peripheral blood of mice. We also find that AZD8055 treatment significantly reduces the number of T helper 1(TH1) cells and TH17 cells and increases regulatory T (Treg) cells in the lamina propria and mesenteric lymph nodes. Furthermore, we demonstrates that AZD8055 suppresses the proliferation of CD4+ and CD8+ T cells and the differentiation of TH1/TH17 cells and expands Treg cells in vitro. The results suggest that, in experimental colitis, AZD8055 exerts anti-inflammatory effect by regulating T helper cell polarization and proliferation.
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Affiliation(s)
- Shurong Hu
- Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
| | - Mengmeng Chen
- Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
| | - Yilin Wang
- Department of Surgery, Cancer hospital, Fudan University, Shanghai, PR China
| | - Zhengting Wang
- Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
| | - Yaofei Pei
- Department of Surgery, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
| | - Rong Fan
- Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
| | - Xiqiang Liu
- Department of Hepatobiliary-Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang Province, PR China
| | - Lei Wang
- Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
| | - Jie Zhou
- Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
| | - Sichang Zheng
- Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
| | - Tianyu Zhang
- Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
| | - Yun Lin
- Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
| | - Maochen Zhang
- Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
| | - Ran Tao
- Department of Hepatobiliary-Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang Province, PR China
| | - Jie Zhong
- Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
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Yamada A, Arakaki R, Saito M, Tsunematsu T, Kudo Y, Ishimaru N. Role of regulatory T cell in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 2016; 22:2195-205. [PMID: 26900284 PMCID: PMC4734996 DOI: 10.3748/wjg.v22.i7.2195] [Citation(s) in RCA: 138] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 11/11/2015] [Accepted: 12/08/2015] [Indexed: 02/06/2023] Open
Abstract
Regulatory T (Treg) cells play key roles in various immune responses. For example, Treg cells contribute to the complex pathogenesis of inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis during onset or development of that disease. Many animal models of IBD have been used to investigate factors such as pathogenic cytokines, pathogenic bacteria, and T-cell functions, including those of Treg cells. In addition, analyses of patients with IBD facilitate our understanding of the precise mechanism of IBD. This review article focuses on the role of Treg cells and outlines the pathogenesis and therapeutic strategies of IBD based on previous reports.
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Liao J, Chang C, Wu H, Lu Q. Cell-based therapies for systemic lupus erythematosus. Autoimmun Rev 2015; 14:43-8. [PMID: 25308529 DOI: 10.1016/j.autrev.2014.10.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Accepted: 09/09/2014] [Indexed: 12/20/2022]
Abstract
Systemic lupus erythematosus (SLE) is a female predominant autoimmune disease characterized by multi-organ disorders. The pathogenesis of SLE is complex. Corticosteroids and immunosuppressive drugs are widely used to treat patients with SLE. However, these indiscriminate suppressors of the immune-mediated inflammatory aberration treat SLE at the cost of considerable adverse effects. Undoubtedly, there is a need for safer and more effective treatments for SLE. Cell-based therapies, although very much in their infancy, are of increasing interest in the treatment of SLE due to their potential for long-term suppression or a possible cure of the disease. Several immunoregulatory cell types, including regulatory T cells, mesenchymal stem cells, B-cells and natural killer cells, have recently been developed as novel products for tolerance-promoting therapies. Here, we provide a brief overview of current research of new cell-based therapeutic approaches that have undergone pre-clinical or clinical trials in the treatment of SLE.
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Delpoux A, Yakonowsky P, Durand A, Charvet C, Valente M, Pommier A, Bonilla N, Martin B, Auffray C, Lucas B. TCR signaling events are required for maintaining CD4 regulatory T cell numbers and suppressive capacities in the periphery. THE JOURNAL OF IMMUNOLOGY 2014; 193:5914-23. [PMID: 25381435 DOI: 10.4049/jimmunol.1400477] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
CD4 regulatory T cells (Tregs) can be subdivided into two subsets according to Ly-6C expression in the periphery. Phenotypic analysis, imaging, and adoptive-transfer experiments of peripheral Ly-6C(-) and Ly-6C(+) Tregs reveal that the nonexpression of Ly-6C by ∼70% of peripheral Tregs depends on TCR signaling events. Interestingly, Ly-6C(-) Tregs express higher surface amounts of key immunosuppressive molecules than do Ly-6C(+) Tregs and produce constitutively anti-inflammatory cytokines. In line with their phenotype, Ly-6C(+) Tregs exhibit poor suppressive capacities in vitro and in vivo. Finally, although Ly-6C(-) Tregs maintain their numbers with age, Ly-6C(+) Tregs gradually disappear. Altogether, our data strongly suggest that both the survival and suppressive functions of peripheral CD4 Tregs rely on their ability to receive strong TCR signals.
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Affiliation(s)
- Arnaud Delpoux
- Institut Cochin, Centre National de la Recherche Scientifique UMR8104, INSERM U1016, Université Paris Descartes, 75014 Paris, France
| | - Philippe Yakonowsky
- Institut Cochin, Centre National de la Recherche Scientifique UMR8104, INSERM U1016, Université Paris Descartes, 75014 Paris, France
| | - Aurélie Durand
- Institut Cochin, Centre National de la Recherche Scientifique UMR8104, INSERM U1016, Université Paris Descartes, 75014 Paris, France
| | - Céline Charvet
- Institut Cochin, Centre National de la Recherche Scientifique UMR8104, INSERM U1016, Université Paris Descartes, 75014 Paris, France
| | - Michael Valente
- Institut Cochin, Centre National de la Recherche Scientifique UMR8104, INSERM U1016, Université Paris Descartes, 75014 Paris, France
| | - Arnaud Pommier
- Institut Cochin, Centre National de la Recherche Scientifique UMR8104, INSERM U1016, Université Paris Descartes, 75014 Paris, France
| | - Nelly Bonilla
- Institut Cochin, Centre National de la Recherche Scientifique UMR8104, INSERM U1016, Université Paris Descartes, 75014 Paris, France
| | - Bruno Martin
- Institut Cochin, Centre National de la Recherche Scientifique UMR8104, INSERM U1016, Université Paris Descartes, 75014 Paris, France
| | - Cédric Auffray
- Institut Cochin, Centre National de la Recherche Scientifique UMR8104, INSERM U1016, Université Paris Descartes, 75014 Paris, France
| | - Bruno Lucas
- Institut Cochin, Centre National de la Recherche Scientifique UMR8104, INSERM U1016, Université Paris Descartes, 75014 Paris, France
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Matricon J, Barnich N, Ardid D. Immunopathogenesis of inflammatory bowel disease. SELF NONSELF 2014; 1:299-309. [PMID: 21487504 DOI: 10.4161/self.1.4.13560] [Citation(s) in RCA: 155] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2010] [Revised: 09/06/2010] [Accepted: 09/07/2010] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD) is a group of idiopathic, chronic and relapsing inflammatory conditions of the gastrointestinal tract. Familial and epidemiological studies have stressed the involvement of genetic factors and have also shown the critical role of environmental factors such as sanitation and hygiene in the development of IBD. However, the molecular mechanisms of intestinal inflammation in IBD have long remained unknown. In recent years, the study of susceptibility genes involved in the detection of bacterial components and in the regulation of the host immune response has shed light onto the potential role of intestinal pathogens and gut flora in IBD immunobiology. This review presents current knowledge on intestinal epithelial barrier alterations and on dysfunction of mucosal innate and acquired immune responses in IBD. The data support the etiological hypothesis which argues that pathogenic intestinal bacteria and/or infectious agents initiate and perpetuate the inflammation of the gut through disruption of tolerance towards the commensal microbiota in an individual with genetic vulnerability.
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Affiliation(s)
- Julien Matricon
- Clermont Université; Université d'Auvergne; Pharmacologie Fondamentale et Clinique de la Douleur; Laboratoire de Pharmacologie Médicale; Inserm U 766; Clermont-Ferrand, France
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Chang JB, Xue R, Zhou ZX, Feng YH, Dai WW, Qiu J, Yang YF. Prediction of antiviral efficacy in patients with chronic hepatitis C by changes in forkhead box protein 3 levels. Exp Ther Med 2014; 8:165-168. [PMID: 24944616 PMCID: PMC4061195 DOI: 10.3892/etm.2014.1675] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 01/31/2014] [Indexed: 01/06/2023] Open
Abstract
The aim of the present study was to investigate the distribution of CD4+CD25+ regulatory T cells (Tregs) in the peripheral blood of patients with chronic hepatitis C; in addition to identifying whether the distribution of CD4+CD25+ Tregs predicts the efficacy of antiviral therapy for HCV. The expression of CD4+CD25+ forkhead box protein (FOXP) 3+ Tregs within a CD4+ T cell population was detected in the peripheral blood obtained from patients with chronic hepatitis C and from healthy control subjects using flow cytometry. The hepatitis C virus (HCV)-RNA load was measured using quantitative-fluorescence polymerase chain reaction. CD4+CD25+FOXP3+ Tregs accounted for 14.24±1.33% of the CD4+ T cells in the peripheral blood of patients with chronic hepatitis C, which was higher than that of the healthy control subjects (5.62±1.21%; P<0.001). Furthermore, the frequency of CD4+CD25+FOXP3+ Tregs in CD4+ T cells of the peripheral blood positively correlated with the HCV-RNA load (r=0.73; P=0.032). Therefore, the results of the present study indicated that the expression of CD4+CD25+FOXP3+ Tregs increased in patients that were chronically infected with HCV and positively correlated with the HCV-RNA load.
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Affiliation(s)
- Jia-Bao Chang
- Department of Liver Disease, The Second Affiliated Hospital, Southeast University, Nanjing, Jiangsu 210007, P.R. China
| | - Rong Xue
- Department of Liver Disease, The Second Affiliated Hospital, Southeast University, Nanjing, Jiangsu 210007, P.R. China
| | - Zhen-Xian Zhou
- Department of Liver Disease, The Second Affiliated Hospital, Southeast University, Nanjing, Jiangsu 210007, P.R. China
| | - Yan-Hong Feng
- Department of Liver Disease, The Second Affiliated Hospital, Southeast University, Nanjing, Jiangsu 210007, P.R. China
| | - Wei-Wei Dai
- Department of Liver Disease, The Second Affiliated Hospital, Southeast University, Nanjing, Jiangsu 210007, P.R. China
| | - Jie Qiu
- Department of Liver Disease, The Second Affiliated Hospital, Southeast University, Nanjing, Jiangsu 210007, P.R. China
| | - Yong-Feng Yang
- Department of Liver Disease, The Second Affiliated Hospital, Southeast University, Nanjing, Jiangsu 210007, P.R. China
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Bhanumathy KK, Zhang B, Ahmed KA, Qureshi M, Xie Y, Tao M, Tan X, Xiang J. Transgene IL-6 enhances DC-stimulated CTL responses by counteracting CD4+25+Foxp3+ regulatory T cell suppression via IL-6-induced Foxp3 downregulation. Int J Mol Sci 2014; 15:5508-21. [PMID: 24690994 PMCID: PMC4013578 DOI: 10.3390/ijms15045508] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Revised: 02/25/2014] [Accepted: 03/06/2014] [Indexed: 11/17/2022] Open
Abstract
Dendritic cells (DCs), the most potent antigen-presenting cells have been extensively applied in clinical trials for evaluation of antitumor immunity. However, the efficacy of DC-mediated cancer vaccines is still limited as they are unable to sufficiently break the immune tolerance. In this study, we constructed a recombinant adenoviral vector (AdVIL-6) expressing IL-6, and generated IL-6 transgene-engineered DC vaccine (DCOVA/IL-6) by transfection of murine bone marrow-derived ovalbumin (OVA)-pulsed DCs (DCOVA) with AdVIL-6. We then assessed DCOVA/IL-6-stimulated cytotoxic T-lymphocyte (CTL) responses and antitumor immunity in OVA-specific animal tumor model. We demonstrate that DCOVA/IL-6 vaccine up-regulates expression of DC maturation markers, secretes transgene-encoded IL-6, and more efficiently stimulates OVA-specific CTL responses and therapeutic immunity against OVA-expressing B16 melanoma BL6-10OVA in vivo than the control DCOVA/Null vaccine. Moreover, DCOVA/IL-6-stimulated CTL responses were relatively maintained in mice with transfer of CD4+25+Foxp3+ Tr-cells, but significantly reduced when treated with anti-IL-6 antibody. In addition, we demonstrate that IL-6 down-regulates Foxp3-expression of CD4+25+Foxp3+ Tr-cells in vitro. Taken together, our results demonstrate that AdV-mediated IL-6 transgene-engineered DC vaccine stimulates potent CTL responses and antitumor immunity by counteracting CD4+25+ Tr immunosuppression via IL-6-induced Foxp3 down-regulation. Thus, IL-6 may be a good candidate for engineering DCs for cancer immunotherapy.
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Affiliation(s)
| | - Bei Zhang
- Cancer Research Unit, Saskatchewan Cancer Agency, Saskatoon, SK S7N 5E5, Canada.
| | | | - Mabood Qureshi
- Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
| | - Yufeng Xie
- Department of Oncology, the First Affiliated Hospital of Soochow University, Soochow 215000, China.
| | - Min Tao
- Department of Oncology, the First Affiliated Hospital of Soochow University, Soochow 215000, China.
| | - Xin Tan
- School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China.
| | - Jim Xiang
- Cancer Research Unit, Saskatchewan Cancer Agency, Saskatoon, SK S7N 5E5, Canada.
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Roles of T cell-associated L-selectin and β7 integrins during induction and regulation of chronic colitis. Inflamm Bowel Dis 2013; 19:2547-59. [PMID: 24132160 DOI: 10.1097/mib.0b013e3182a8df0a] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND L-selectin (CD62L) and β(7) integrins are important for trafficking of naive T cells under steady-state conditions. The objectives of this study were to dissect the requirements for T cell-associated CD62L and β(7) integrins during initiation, progression, and regulation of chronic colitis. METHODS Using the T-cell transfer model, we compared colitogenic potential between T cells lacking one or both of these molecules with wild-type T cells. To assess trafficking of cells to the secondary lymphoid tissue and the gut, we performed co-homing experiments. RESULTS Adoptive transfer of wild-type, CD62L(-/-) or β(7)(-/-) single-deficient T cells induced moderate to severe disease with slightly different kinetics. However, transfer of CD62L(-/-) β(7)(-/-) double-deficient (DKO) T cells produced significantly attenuated gut inflammation, which correlated with fewer T cells and reduced levels of proinflammatory cytokines in the colon lamina propria. Our subsequent experiments established that lack of colitogenic potential of these cells was due to inability of DKO T cells to home to the secondary lymphoid tissue. Furthermore, homing of in vitro-generated effector DKO T cells to the inflamed intestine was significantly impaired. Lastly, DKO regulatory T cells were ineffective at suppressing colitis induced by wild-type T cells. CONCLUSIONS We established that T cells can use either CD62L(-/-) or β(7)(-/-) integrins to induce chronic colitis, but lack of both abrogates their colitogenic potential. Effector T cells critically rely on β(7) integrin during their recruitment to the inflamed intestinal mucosa. Finally, regulation of intestinal inflammation by regulatory T cells requires one or both of these adhesion molecules.
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Highly self-reactive naive CD4 T cells are prone to differentiate into regulatory T cells. Nat Commun 2013; 4:2209. [DOI: 10.1038/ncomms3209] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Accepted: 06/26/2013] [Indexed: 02/06/2023] Open
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Tamoutounour S, Henri S, Lelouard H, de Bovis B, de Haar C, van der Woude CJ, Woltman AM, Reyal Y, Bonnet D, Sichien D, Bain CC, Mowat AM, Reis e Sousa C, Poulin LF, Malissen B, Guilliams M. CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1-inducing role of mesenteric lymph node macrophages during colitis. Eur J Immunol 2012; 42:3150-66. [PMID: 22936024 DOI: 10.1002/eji.201242847] [Citation(s) in RCA: 425] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2012] [Revised: 08/26/2012] [Accepted: 08/28/2012] [Indexed: 12/17/2022]
Abstract
Dendritic cells (DCs) and monocyte-derived macrophages (MΦs) are key components of intestinal immunity. However, the lack of surface markers differentiating MΦs from DCs has hampered understanding of their respective functions. Here, we demonstrate that, using CD64 expression, MΦs can be distinguished from DCs in the intestine of both mice and humans. On that basis, we revisit the phenotype of intestinal DCs in the absence of contaminating MΦs and we delineate a developmental pathway in the healthy intestine that leads from newly extravasated Ly-6C(hi) monocytes to intestinal MΦs. We determine how inflammation impacts this pathway and show that T cell-mediated colitis is associated with massive recruitment of monocytes to the intestine and the mesenteric lymph node (MLN). There, these monocytes differentiate into inflammatory MΦs endowed with phagocytic activity and the ability to produce inducible nitric oxide synthase. In the MLNs, inflammatory MΦs are located in the T-cell zone and trigger the induction of proinflammatory T cells. Finally, T cell-mediated colitis develops irrespective of intestinal DC migration, an unexpected finding supporting an important role for MLN-resident inflammatory MΦs in the etiology of T cell-mediated colitis.
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Affiliation(s)
- Samira Tamoutounour
- Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France
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Xu T, Duan Q, Wang G, Hu B. CD4 + CD25high regulatory T cell numbers and FOXP3 mRNA expression in patients with advanced esophageal cancer before and after chemotherapy. Cell Biochem Biophys 2011; 61:389-392. [PMID: 21607687 DOI: 10.1007/s12013-011-9197-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
We evaluated the changes in CD4 + CD25(high) regulatory T (Treg) cells and FOXP3 mRNA expression in patients with advanced esophageal cancer as well as its clinical significance. For this purpose, the frequencies of peripheral blood Treg cells in 68 patients with advanced esophageal cancer and 40 healthy controls were determined by flow cytometry, and FOXP3 mRNA expression in Treg cells of 40 patients was determined by RT-PCR. The data show that Treg cell numbers were significantly higher (P < 0.01) in esophageal cancer patients (1.82 ± 0.54% of CD4 + T cells) as compared with healthy controls (1.52 ± 0.70% of CD4(+) T cells). Treg cell numbers in the patients were significantly higher (P < 0.05) before chemotherapy (1.82 ± 0.54% of CD4 + T cells) than after chemotherapy (1.66 ± 0.58% of CD4 + T cells). Expression of the FOXP3 mRNA in the patients was significantly lower (P < 0.05) after chemotherapy (0.266 ± 0.028% of CD4 + T cells) than before chemotherapy (0.318 ± 0.027% of CD4 + T cells). It was, therefore, concluded that Treg cell numbers as well as FOXP3 mRNA expression in advanced esophageal cancer patients were significantly decreased after chemotherapy. Notably, FOXP3 gene may thus be involved in regulating the numbers and function of Treg cells in advanced esophageal cancer patients receiving chemotherapy.
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Affiliation(s)
- Tengyun Xu
- Department of Oncology, Anhui Medical University Affiliated Anhui Provincial Hospital, Hefei, Anhui, China.
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El Essawy B, Putheti P, Gao W, Strom TB. Rapamycin generates graft-homing murine suppressor CD8(+) T cells that confer donor-specific graft protection. Cell Transplant 2011; 20:1759-69. [PMID: 21439133 DOI: 10.3727/096368911x566244] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
It has been reported that rapamycin (RPM) can induce de novo conversion of the conventional CD4(+)Foxp3(-) T cells into CD4(+)Foxp3(+) regulatory T cells (iTregs) in transplantation setting. It is not clear whether RPM can similarly generate suppressor CD8(+) T cells to facilitate graft acceptance. In this study, we investigated the ability of short-term RPM treatment in promoting long-term acceptance (LTA) of MHC-mismatched skin allografts by generating a CD8(+) suppressor T-cell population. We found that CD4 knockout (KO) mice (in C57BL/6 background, H-2(b)) can promptly reject DBA/2 (H-2(d)) skin allografts with mean survival time (MST) being 13 days (p < 0.01). However, a short course RPM treatment in these animals induced LTA with graft MST longer than 100 days. Adoptive transfer of CD8(+) T cells from LTA group into recombination-activating gene 1 (Rag-1)-deficient mice provided donor-specific protection of DBA/2 skin grafts against cotransferred conventional CD8(+) T cells. Functionally active immunoregulatory CD8(+) T cells also resided in donor skin allografts. Eighteen percent of CD8(+) suppressor T cells expressed CD28 as measured by flow cytometry, and produced reduced levels of IFN-γ, IL-2, and IL-10 in comparison to CD8(+) effector T cells as measured by ELISA. It is unlikely that CD8(+) suppressor T cells mediated graft protection via IL-10, as IL-10/Fc fusion protein impaired RPM-induced LTA in CD4 KO mice. Our data supported the notion that RPM-induced suppressor CD8(+) T cells home to the allograft and exert donor-specific graft protection.
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Affiliation(s)
- Basset El Essawy
- Department of Medicine, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Ostanin DV, Brown CM, Gray L, Bharwani S, Grisham MB. Evaluation of the immunoregulatory activity of intraepithelial lymphocytes in a mouse model of chronic intestinal inflammation. Int Immunol 2010; 22:927-39. [PMID: 21071622 DOI: 10.1093/intimm/dxq447] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Intraepithelial lymphocytes (IELs) represent the first line of lymphocyte defense against the intestinal bacteria. Although previous studies have demonstrated a protective role of IELs in the development of colitis, the data supporting a regulatory role for IELs are limited. The objective of this study was to examine the suppressive activity of IELs in vitro and in vivo using a mouse model of chronic small and large bowel inflammation. Adoptive transfer of CD8α(+) IELs isolated from small intestines of wild-type (WT) mice into TCR βxδ-deficient (TCR βxδ(-/-)) recipients did not prevent or delay the onset of the disease induced by WT CD4(+)CD45RB(high) T cells. On the contrary, we observed a more rapid onset of wasting and clinical signs of intestinal inflammation when compared with animals injected with CD4(+)CD45RB(high) T cells alone. Histopathological scores of small and large bowel did not differ significantly between the two groups. Transfer of IELs alone did not produce any pathological changes. Real-time PCR analysis of intestinal tissues showed up-regulation of message for T(h)1- and macrophage-derived cytokines in colon and small bowel. Using Foxp3-GFP reporter mice, we were unable to detect any Foxp3(+) cells within the CD8α(+) IELs but did find a small population of Foxp3(+)CD4(+) IELs in the small and large bowel. Using in vitro suppression assay, we found that neither TCRαβ(+)CD8αα(+), TCRαβ(+)CD8αβ(+) nor TCRγδ(+)CD8αα(+) IELs were capable of suppressing CD4(+) T-cell proliferation. Taken together, our data do not support an immunoregulatory role for CD8α(+) IELs in a mouse model of small and large bowel inflammation.
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Affiliation(s)
- D V Ostanin
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, PO Box 33932, Shreveport, LA 71130-3932, USA.
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Kim BJ, Jones HP. Epinephrine-primed murine bone marrow-derived dendritic cells facilitate production of IL-17A and IL-4 but not IFN-γ by CD4+ T cells. Brain Behav Immun 2010; 24:1126-36. [PMID: 20621581 PMCID: PMC2939238 DOI: 10.1016/j.bbi.2010.05.003] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2010] [Revised: 05/19/2010] [Accepted: 05/21/2010] [Indexed: 12/14/2022] Open
Abstract
Sympathetic activation leading to the release of epinephrine and norepinephrine, is known as an important regulatory circuit related to immune-mediated diseases. However, questions still remain on the behavior of antigen presenting cells (APC) dictated by stress-induced sympathetic neurotransmitters. The purpose of this study was to examine the fate of bone marrow-derived dendritic cell (BMDC)-associated influences on resting CD4(+) T cell activation. We hypothesize that pre-exposure of dendritic cells (DCs) can modify the intensity of cytokine production, leading to preference in resting CD4(+) T cell activation. BMDCs were pre-treated with epinephrine for 2h followed by subsequent treatment of lipopolysaccharide (LPS). Subsequently, BMDCs were cocultured with purified CD4(+) T cells from mouse spleen in the absence or presence of anti-CD3 stimulation in epinephrine-free media. Epinephrine pre-treatment enhanced surface expression of MHCII, CD80 and CD86. Quantitative RT-PCR showed that epinephrine pre-treatment induced a significant transcriptional decrease of IL-12p40 and a significant increase of IL-12p35 and IL-23p19. In addition, β2-adrenergic-blockade was shown to reverse these effects. Epinephrine pre-treatment also induced a significant decrease of IL-12p70 and a significant increase of IL-23 and IL-10 cytokine production. Importantly, these changes corresponded with increased IL-4 and IL-17A, but not IFN-g cytokine production by CD4(+) T cells in a b2-adrenergic receptor-dependent manner. These results suggest that exposure to stress-derived epinephrine dictates dendritic cells to generate a dominant Th2/Th17 phenotype in the context of subsequent exposure to a pathogenic stimulus.
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Affiliation(s)
| | - Harlan P. Jones
- Correspondence; Harlan P. Jones, Ph.D., Assistant Professor, Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, Texas 76107, USA, , Telephone: (817) 735-2448, Fax: (817) 735-2133
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Carlier VA, Vanderelst LP, Jacquemin MG, Saint-Remy JMR. Regulatory CD4+ T cells in allergic asthma. Expert Rev Clin Immunol 2010; 2:737-44. [PMID: 20477629 DOI: 10.1586/1744666x.2.5.737] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Active suppression by regulatory T cells (T(regs)) appears to play a key role in the downregulation of T-cell responses to foreign antigens. Several subtypes of T(regs) have been described but their mechanisms of action remain unclear. Recent data demonstrate that the suppressive capacity of natural T(regs) could be associated with cytotoxicity due to the release of granzymes, which are capable of apoptosis induction in target effector T lymphocytes and in antigen-presenting cells, such as dendritic cells. The mechanism of such nonspecific T(regs) is discussed. Peptide immunotherapy is thought to induce regulatory cells capable of suppressing autoimmune and allergic diseases. We have recently optimized a vaccination strategy by which cytotoxic antigen-specific adaptive T(regs) can be elicited towards allergens involved in allergic asthma. Such a strategy could be of value in the treatment of allergic asthma.
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Affiliation(s)
- Vincent A Carlier
- University of Leuven, Center for Molecular and Vascular Biology, Campus Gasthuisberg, O&N, Herestraat 49, 3000 Leuven, Belgium.
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Roncagalli R, Mingueneau M, Grégoire C, Malissen M, Malissen B. LAT signaling pathology: an "autoimmune" condition without T cell self-reactivity. Trends Immunol 2010; 31:253-9. [PMID: 20542732 DOI: 10.1016/j.it.2010.05.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2010] [Revised: 04/27/2010] [Accepted: 05/03/2010] [Indexed: 01/18/2023]
Abstract
Partial loss-of-function mutations in several molecules involved in T-cell receptor (TCR) signaling result in inflammation and autoimmunity. How can mutations that reduce TCR signaling output, paradoxically lead to immune pathology? This review summarizes experiments demonstrating that mutations in the linker for activation of T cells (LAT) predispose toward aberrant T cell responses to antigen in the presence of normal thymic selection. In the absence of LAT, antigen-specific T cells give rise to self-perpetuating pro-inflammatory responses and induce the production of autoantibodies independently of TCR engagement. Therefore, some pathological conditions called "autoimmune" might not result from the presence of self-reactive T cells, but from defective mechanisms that normally keep T cell activation in check.
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Affiliation(s)
- Romain Roncagalli
- Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Case 906, 13288 Marseille Cedex 9, France
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30
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Zheng W, Wang QH, Feng H, Liu J, Meng HR, Cao YM. CD4+CD25+Foxp3+ regulatory T cells prevent the development of Th1 immune response by inhibition of dendritic cell function during the early stage of Plasmodium yoelii infection in susceptible BALB/c mice. Folia Parasitol (Praha) 2010; 56:242-50. [PMID: 20128236 DOI: 10.14411/fp.2009.028] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Protective immunity against murine malaria infection depends largely on the establishment of effective Th1 immune response during the early stages of infection. Experimental data suggest that the death of Plasmodium yoelii 17XL (Py 17XL) susceptible BALB/c mice results from the suppression of Th1 immune response mediated by CD4+CD25+Foxp3+ regulatory T cells (Tregs). However, the mechanism by which Tregs regulate Th1 immune response is poorly understood. Since immunity is initiated by dendritic cells (DCs), we analysed DC responses to Py 17XL in control and Treg-depleted BALB/c mice. Myeloid DC proliferation, phenotypic maturation and interleukin-12 (IL-12) production were strongly inhibited in control BALB/c mice. In contrast, plasmacytoid DC proliferation and IL-10 production were strongly enhanced in control BALB/c mice. In-vivo depletion of Tregs resulted in significantly reversed inhibition of DC response, which may contribute to the establishment of Th1 immune response, indicating that Tregs contribute to the suppression of Th1 immune response during malaria. These findings suggest Tregs contribute to prevent Th1 immune response establishment during the early stage of Py 17XL infection by inhibiting DC response.
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Affiliation(s)
- Wei Zheng
- Department of Immunology, College of Basic Medical Sciences, China Medical University, Shenyang, China
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31
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Lemus JA, Vergara P, Fargallo JA. Response of circulating T-lymphocytes to a coccidian infection: insights from a parasitization-vaccination experiment. Funct Ecol 2010. [DOI: 10.1111/j.1365-2435.2009.01681.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Roncagalli R, Mingueneau M, Grégoire C, Langlet C, Malissen B, Malissen M. Lymphoproliferative disorders involving T helper effector cells with defective LAT signalosomes. Semin Immunopathol 2010; 32:117-25. [PMID: 20107804 DOI: 10.1007/s00281-009-0195-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2009] [Accepted: 12/29/2009] [Indexed: 10/19/2022]
Abstract
Linker for activation of T cells (LAT) is a membrane adaptor protein that is expressed in T cells and coordinates the assembly of a multiprotein complex-the LAT signalosome-that links the T cell-specific and the ubiquitous components of the T cell antigen receptor (TCR) signaling pathway. The present review focuses on recent LAT knock-in mice that were found to develop lymphoproliferative disorders involving polyclonal CD4(+) T cells that produced excessive amounts of T helper-type 2 cytokines. These mouse models revealed that LAT constitutes more than just a positive regulator of TCR signaling and plays a negative regulatory role that contributes to terminate antigen-driven T cell responses by exerting a repressive function on components of the TCR signaling cassette that lie upstream of LAT or function independently of LAT. In the absence of such a LAT-operated negative regulatory loop that is intrinsic to conventional CD4(+) T cells and of no lesser importance than the extrinsic regulatory mechanisms mediated by regulatory T cells, physiologic, antigen-specific CD4(+) T cell responses evolve into chronic pro-inflammatory responses that perpetuate themselves in a manner that does not depend on engagement of the TCR and that induce the production of massive amounts of antibodies and autoantibodies in a major histocompatibility complex-II-independent, "quasi-mitogenic" mode. As discussed, these data underscore that a novel immunopathology proper to defective LAT signalosomes is likely taking shape, and we propose to call it "LAT signaling pathology."
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Affiliation(s)
- Romain Roncagalli
- Centre d'Immunologie de Marseille-Luminy, Case 906, Université de la Méditerranée, 13288, Marseille Cedex 9, France
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Induction and cellular expression of tartrate resistant acid phosphatase during dextran sodium sulphate induced colitis in rats. Histochem Cell Biol 2009; 132:599-612. [PMID: 19821118 DOI: 10.1007/s00418-009-0647-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/23/2009] [Indexed: 01/28/2023]
Abstract
The aim of this study was to investigate the cellular and molecular expression of tartrate resistant acid phosphatase (TRAP) as a marker of activated macrophages in macrophage dependent dextran sulphate sodium (DSS)-induced colitis in rats. In normal colon, TRAP+/CX(3)CR(1)+ macrophages were located in the upper part of the lamina propria. In the early stage (day 1-3) of acute colitis prior to histopathological changes, induction of the cytokines TNFalpha, IL-12 and IFN gamma occurred concomitant with increased mRNA and enzyme activity of TRAP along with a slight increase of TRAP immunolabelling in macrophages of the upper lamina propria, suggesting induction of TRAP in resident macrophages. Among these cytokines, TNFalpha up-regulated TRAP expression in the RAW 264.7 monocyte/macrophage cell line. In a later phase (day 7) with fulminant colitis, a massive infiltration of macrophages including recruited TRAP+/CCR2+ cells was observed also in the lower part of the lamina propria as well as in the submuscular layer. Additionally, differentiated cellular expression of pro- and mature TRAP also suggest that mucosal macrophages in the lower part of lamina propria bordering the sub-mucosa provide a source of replenishment of macrophages situated in the upper lamina propria. In conclusion, induction of TRAP provides an early sign of macrophage responsiveness in DSS induced colitis.
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Lymphocyte proliferation in immune-mediated diseases. Trends Immunol 2009; 30:430-8. [PMID: 19699149 DOI: 10.1016/j.it.2009.06.002] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2009] [Revised: 06/21/2009] [Accepted: 06/24/2009] [Indexed: 12/21/2022]
Abstract
Defects in T cell homeostatic mechanisms can result in T cell lymphopenia, defined as decreased numbers of lymphocytes. Lymphopenia results in homeostatic proliferation in order to maintain T cell homeostasis. It has been proposed that homeostatic proliferation can expand the pool of autoreactive T cells that promote autoimmunity, and indeed recent studies have further substantiated this observation in both animal models and humans. Conversely, homeostatic proliferation can promote tumor immunity by allowing tumor-specific T cells to accumulate. In this review, we discuss how the outcome of homeostatic proliferation can function both in a deleterious manner in autoimmunity and a beneficial way in tumor immunity. We also discuss the roles of various cytokines and T regulatory cells that control homeostatic proliferation.
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Mingueneau M, Roncagalli R, Grégoire C, Kissenpfennig A, Miazek A, Archambaud C, Wang Y, Perrin P, Bertosio E, Sansoni A, Richelme S, Locksley RM, Aguado E, Malissen M, Malissen B. Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors that function independently of the T cell receptor. Immunity 2009; 31:197-208. [PMID: 19682930 DOI: 10.1016/j.immuni.2009.05.013] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2008] [Revised: 04/13/2009] [Accepted: 05/13/2009] [Indexed: 01/18/2023]
Abstract
Despite compromised T cell antigen receptor (TCR) signaling, mice in which tyrosine 136 of the adaptor linker for activation of T cells (LAT) was constitutively mutated (Lat(Y136F) mice) accumulate CD4(+) T cells that trigger autoimmunity and inflammation. Here we show that equipping postthymic CD4(+) T cells with LATY136F molecules or rendering them deficient in LAT molecules triggers a lymphoproliferative disorder dependent on prior TCR engagement. Therefore, such disorders required neither faulty thymic T cell maturation nor LATY136F molecules. Unexpectedly, in CD4(+) T cells recently deprived of LAT, the proximal triggering module of the TCR induced a spectrum of protein tyrosine phosphorylation that largely overlapped the one observed in the presence of LAT. The fact that such LAT-independent signals result in lymphoproliferative disorders with excessive cytokine production demonstrates that LAT constitutes a key negative regulator of the triggering module and of the LAT-independent branches of the TCR signaling cassette.
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Affiliation(s)
- Michael Mingueneau
- Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Case 906, 13288 Marseille Cedex 9, France
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36
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Effects of CD4+CD25+Foxp3+regulatory T cells on earlyPlasmodium yoelii17XL infection in BALB/c mice. Parasitology 2009; 136:1107-20. [DOI: 10.1017/s0031182009990370] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
SUMMARYThe outcome ofPlasmodium yoelii17XL-infected BALB/c and DBA/2 mice, ranging from death to spontaneous cure, respectively, depends largely on the establishment of effective pro-inflammatory type 1 responses during the early stages of infection and associates with CD4+CD25+Foxp3+regulatory T cells (Tregs). Here, effects of Tregs were analysed on earlyP. yoelii17XL infection in BALB/c and DBA/2 mice.In vivodepletion of Tregs significantly reversed the inhibited establishment of effective pro-inflammatory type 1 responses in BALB/c mice, indicating that this cell population contributed to the suppression of T-cell function in malaria. Moreover, the proportion and absolute numbers of IL-10-secreting Tregs in BALB/c mice were significantly higher than that found in DBA/2 mice by intracytoplasmic staining, and IL-10 production was correlated with the Tregs population. In addition,in vivoTregs depletion decreased the production of IL-10 and the apoptosis of CD4+T cells. Consistently, IL-10R blockade also had the same effect as that of Tregs depletion inP. yoelii17XL-infected BALB/c mice. Our data demonstrate that Tregs perhaps have an important role in regulating pro-inflammatory type 1 responses in an IL-10-dependent manner and induce CD4+T cell apoptosis during the early stage ofP. yoelii17XL infection.
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Saruta M, Targan SR, Mei L, Ippoliti AF, Taylor KD, Rotter JI. High-frequency haplotypes in the X chromosome locus TLR8 are associated with both CD and UC in females. Inflamm Bowel Dis 2009; 15:321-7. [PMID: 18942751 PMCID: PMC2643315 DOI: 10.1002/ibd.20754] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND TNF-alpha and IL-1 have been associated with mucosal inflammation in both Crohn's disease (CD) and ulcerative colitis (UC). Innate immune defects have been associated with CD, specifically CARD15/NOD2. Recently, Toll-like receptor 8 (TLR8) signaling has been shown to enhance generation of both cytokines. Interestingly, TLR8 is located on the X chromosome and inflammatory bowel disease (IBD) has been associated with abnormalities of the X chromosome. The aim was to test whether TLR8 haplotypes are associated with IBD. METHODS Subjects (735 CD, 343 UC, 245 controls) were genotyped. Single nucleotide polymorphisms (SNPs) were chosen to tag common Caucasian haplotypes. RESULTS Both "risk (H4)" and "protective (H1)" TLR8 haplotypes were observed associated with CD in females. Eighteen percent of CD females had H4 compared with 9% of controls (P = 0.02). Fifty-nine percent of CD females had H1 compared with 72% of controls (P = 0.01). H1 was also negatively associated with UC in females (59% of UC, 72% of controls P = 0.03). Diplotype analysis of CD, UC, and all IBD in females revealed that 2 protective haplotypes (H1/H1) had a markedly diminished odds ratio, 0.4-0.5. The presence of a risk haplotype (H4 / not H1) had a significantly increased odds ratio, 2.0-2.2. Thus, the risk for IBD was 4-5 times higher in females with 1 risk haplotype than with the protective/protective diplotype. CONCLUSIONS TLR8 is an X-linked IBD susceptibility gene with both common predisposing and protecting haplotypes. These associations further emphasize the importance of genetic variation in innate immunity as determinants, not only of CD, but of UC as well.
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Affiliation(s)
- Masayuki Saruta
- Inflammatory Bowel Disease Research Center, Cedars-Sinai Medical Center and the UCLA School of Medicine, Los Angeles, California 90048, USA
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Abstract
The peripheral mature T cell pool is regulated by complex homeostatic mechanisms. Naive T cells are maintained by interleukin-7 (IL-7) and T cell receptor (TCR) signaling from contact with major histocompatibility complex (MHC), which sustain expression of antiapoptotic molecules and allow the cells to survive in interphase. Competition for these ligands declines when T cell numbers are reduced and causes residual naive T cells to proliferate and differentiate into memory-like cells. This memory cell population is thus heterogeneous and comprised of cells derived from responses to both foreign and self-antigens. Typical memory cells are kept alive and induced to divide intermittently by a mixture of IL-7 and IL-15. This review highlights recent advances in how naive and memory T cell homeostasis is regulated.
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Affiliation(s)
- Charles D Surh
- The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
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Yolcu ES, Ash S, Kaminitz A, Sagiv Y, Askenasy N, Yarkoni S. Apoptosis as a mechanism of T‐regulatory cell homeostasis and suppression. Immunol Cell Biol 2008; 86:650-8. [DOI: 10.1038/icb.2008.62] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Esma S Yolcu
- Department of Microbiology and Immunology, Institute for Cellular Therapeutics, University of LouisvilleLouisvilleKYUSA
| | - Shifra Ash
- Frankel Laboratory for Experimental Bone Marrow Transplantation, Center for Stem Cell Research, Schneider Children's Medical Center of IsraelPetach TikvaIsrael
| | - Ayelet Kaminitz
- Frankel Laboratory for Experimental Bone Marrow Transplantation, Center for Stem Cell Research, Schneider Children's Medical Center of IsraelPetach TikvaIsrael
| | | | - Nadir Askenasy
- Frankel Laboratory for Experimental Bone Marrow Transplantation, Center for Stem Cell Research, Schneider Children's Medical Center of IsraelPetach TikvaIsrael
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Yarkoni S, Kaminitz A, Sagiv Y, Yaniv I, Askenasy N. Involvement of IL-2 in homeostasis of regulatory T cells: the IL-2 cycle. Bioessays 2008; 30:875-88. [DOI: 10.1002/bies.20812] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Winstead CJ, Fraser JM, Khoruts A. Regulatory CD4+CD25+Foxp3+ T cells selectively inhibit the spontaneous form of lymphopenia-induced proliferation of naive T cells. THE JOURNAL OF IMMUNOLOGY 2008; 180:7305-17. [PMID: 18490730 DOI: 10.4049/jimmunol.180.11.7305] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Regulatory CD4(+)CD25(+)Foxp3(+) T cells play a critical role in controlling autoimmunity and T cell homeostasis. However, their role in regulation of lymphopenia-induced proliferation (LIP), a potential mechanism for generation of autoaggressive T cells, has been poorly defined. Currently, two forms of LIP are recognized: spontaneous and homeostatic. Spontaneous LIP is characterized by fast, burst-like cell-cycle activity, and may allow effector T cell differentiation. Homeostatic LIP is characterized by slow and steady cell cycle activity and is not associated with the acquisition of an effector phenotype. In this study, we demonstrate that CD4(+)CD25(+)Foxp3(+) T cells suppress the spontaneous, but not homeostatic, LIP of naive CD8 and CD4 T cells. However, selective inhibition of spontaneous LIP does not fully explain the tolerogenic role of Tregs in lymphopenia-associated autoimmunity. We show here that suppression of LIP in the lymphoid tissues is independent of Treg-derived IL-10. However, IL-10-deficient Tregs are partially defective in their ability to prevent colitis caused by adoptive transfer of CD4 T cells into RAG(-/-) mice. We propose that Tregs may inhibit emergence of effector T cells during the inductive phase of the immune response in the secondary lymphoid tissues by IL-10-independent mechanisms. In contrast, Treg-mediated inhibition of established effector T cells does require IL-10. Both Treg functions appear to be important in control of lymphopenia-associated autoimmunity.
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Affiliation(s)
- Colleen J Winstead
- Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
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42
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Ishimaru N, Yamada A, Kohashi M, Arakaki R, Takahashi T, Izumi K, Hayashi Y. Development of inflammatory bowel disease in Long-Evans Cinnamon rats based on CD4+CD25+Foxp3+ regulatory T cell dysfunction. THE JOURNAL OF IMMUNOLOGY 2008; 180:6997-7008. [PMID: 18453622 DOI: 10.4049/jimmunol.180.10.6997] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
A mutant strain with defective thymic selection of the Long-Evans Cinnamon (LEC) rat was found to spontaneously develop inflammatory bowel disease (IBD)-like colitis. The secretion of Th1-type cytokines including IFN-gamma and IL-2 from T cells of mesenteric lymph node cells (MLNs) and lamina propria mononuclear cells, but not spleen cells, in LEC rats was significantly increased more than that of the control Long-Evans Agouti rats through up-regulated expression of T-bet and phosphorylation of STAT-1 leading to NF-kappaB activation. In addition, the number of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells of the thymus, MLNs, and lamina propria mononuclear cells from LEC rats was significantly reduced, comparing with that of the control rats. Moreover, bone marrow cell transfer from LEC rats into irradiated control rats revealed significantly reduced CD25(+)Foxp3(+) Treg cells in thymus, spleen, and MLNs compared with those from control rats. Indeed, adoptive transfer with T cells of MLNs, not spleen cells, from LEC rats into SCID mice resulted in the development of inflammatory lesions resembling the IBD-like lesions observed in LEC rats. These results indicate that the dysfunction of the regulatory system controlled by Treg cells may play a crucial role in the development of IBD-like lesions through up-regulated T-bet, STAT-1, and NF-kappaB activation of peripheral T cells in LEC rats.
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Affiliation(s)
- Naozumi Ishimaru
- Department of Oral Molecular Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramotocho, Tokushima, Japan.
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Sydora BC, MacFarlane SM, Tavernini MM, Doyle JSG, Fedorak RN. CD4+CD25+ regulatory T cells have divergent effects on intestinal inflammation in IL-10 gene-deficient mice. Dig Dis Sci 2008; 53:1544-52. [PMID: 17990114 DOI: 10.1007/s10620-007-0064-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2007] [Accepted: 10/04/2007] [Indexed: 12/09/2022]
Abstract
The regulatory effect of murine CD4+CD25+ T-cells in vivo appears to be dependent on the secretion of IL-10. The lack of IL-10 in the IL-10 gene-deficient mouse has a profoundly negative effect on the mouse's regulation of the response to intestinal bacteria, resulting in severe enterocolitis. We investigated the effect of neonatal injection with wild-type CD4+CD25+ T-cells on the intestinal immune response in IL-10 gene-deficient mice. At the time of analysis, 8-15 weeks later, all mice demonstrated an increased, antigen-stimulated systemic response. However, the intestinal response was divergent with about half of the mice developing an intestinal inflammation with a high injury score, the other half demonstrating a remarkable reduction in injury score with a marked decrease in intestinal IFNgamma release. Our data demonstrate that CD4+CD25+ T-cells can be activated in IL-10 gene-deficient mice and that this stimulation under stringent conditions has the potential to reduce intestinal inflammation.
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Affiliation(s)
- Beate C Sydora
- Department of Medicine, Division of Gastroenterology, Center of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Zeidler Ledcor Building, Edmonton, Alberta, Canada.
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Poitrasson-Rivière M, Bienvenu B, Le Campion A, Bécourt C, Martin B, Lucas B. Regulatory CD4+ T Cells Are Crucial for Preventing CD8+ T Cell-Mediated Autoimmunity. THE JOURNAL OF IMMUNOLOGY 2008; 180:7294-304. [DOI: 10.4049/jimmunol.180.11.7294] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Begg DJ, Whittington RJ. Experimental animal infection models for Johne’s disease, an infectious enteropathy caused by Mycobacterium avium subsp. paratuberculosis. Vet J 2008; 176:129-45. [PMID: 17449304 DOI: 10.1016/j.tvjl.2007.02.022] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2006] [Revised: 01/30/2007] [Accepted: 02/24/2007] [Indexed: 11/20/2022]
Abstract
A critical literature review of experimental infection models for Johne's disease in farm and laboratory animals was conducted. A total of 73 references were admitted. They were published between 1938 and 2006 and covered species as diverse as cattle, sheep, goats, deer, mice, pigs and others. The factors that appeared to influence the outcome of experimental infections with Mycobacterium avium subsp. paratuberculosis (Mptb) were the species, breed and age of subject used for the infection, the route of infection, and the strain, dose and number of doses of Mptb used to inoculate the subjects. Natural paratuberculosis infection passes through stages, generally over a period measured in years. However, the endpoints chosen by researchers using experimental infections have been determined by the need for immunological, microbiological, pathological or clinical outcomes, and these were the likely factors determining the duration of the trials. Studies have been lacking in the use of a defined type strain of Mptb in pure culture prepared from an archived seed stock of Mptb that can be used at the same passage level in a later trial. Replication of experimental groups has been very uncommon, temporal replication equally rare, as have sufficiently long time scales so as to be able to observe a full range of immunological and pathological changes at different stages of the disease process. While it may be difficult to develop a satisfactory experimental infection model, there is room for improvement in the way experiments have been designed and carried out to date. Choice of animal species/breed of host and strain of Mptb used in an experimental model should be based on the purpose of the study (for example, vaccine efficacy trial, diagnostic test evaluation, pathogenesis study) and local needs. The strain of Mptb used should be typed using IS900 RFLP analysis, IS1311 sequence analysis and other genotypic methods, and preferably be from an archived low passage pure culture with viable bacteria enumerated using a sensitive method rather than from an uncharacterised and unrepeatable tissue homogenate. It is generally agreed that the faecal-oral route is the most important natural route of exposure and the oral route is therefore the preferred route of experimental inoculation to achieve Johne's disease that closely resembles natural infection.
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Affiliation(s)
- Douglas J Begg
- Farm Animal and Veterinary Public Health, Faculty of Veterinary Science, University of Sydney, Australia
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Sojka DK, Huang YH, Fowell DJ. Mechanisms of regulatory T-cell suppression - a diverse arsenal for a moving target. Immunology 2008; 124:13-22. [PMID: 18346152 DOI: 10.1111/j.1365-2567.2008.02813.x] [Citation(s) in RCA: 266] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Naturally-occurring regulatory T cells (Tregs) are emerging as key regulators of immune responses to self-tissues and infectious agents. Insight has been gained into the cell types and the cellular events that are regulated by Tregs. Indeed, Tregs have been implicated in the control of initial activation events, proliferation, differentiation and effector function. However, the mechanisms by which Tregs disable their cellular targets are not well understood. Here we review recent advances in the identification of distinct mechanisms of Treg action and of signals that enable cellular targets to escape regulation. Roles for inhibitory cytokines, cytotoxic molecules, modulators of cAMP and cytokine competition have all been demonstrated. The growing number of inhibitory mechanisms ascribed to Tregs suggests that Tregs take a multi-pronged approach to immune regulation. It is likely that the relative importance of each inhibitory mechanism is context dependent and modulated by the inflammatory milieu and the magnitude of the immune response. In addition, the target cell may be differentially susceptible or resistant to distinct Treg mechanisms depending on their activation or functional status at the time of the Treg encounter. Understanding when and where each suppressive tool is most effective will help to fine tune therapeutic strategies to promote or constrain specific arms of Treg suppression.
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Affiliation(s)
- Dorothy K Sojka
- David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14624, USA
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Hansen W, Westendorf AM, Reinwald S, Bruder D, Deppenmeier S, Groebe L, Probst-Kepper M, Gruber AD, Geffers R, Buer J. Chronic antigen stimulation in vivo induces a distinct population of antigen-specific Foxp3 CD25 regulatory T cells. THE JOURNAL OF IMMUNOLOGY 2008; 179:8059-68. [PMID: 18056346 DOI: 10.4049/jimmunol.179.12.8059] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The concept of immune regulation/suppression has been well-established and, besides thymus-derived CD4+CD25+ regulatory T (TR) cells, it became clear that a variety of additional peripherally induced TR cells play vital roles in protection from many harmful immune responses including intestinal inflammation. In the present study, we have analyzed in vivo-induced Ag-specific CD4+ TR cells with respect to their molecular and functional phenotype. By comparative genomics we could show that these Ag-specific TR cells induced by chronic Ag stimulation in vivo clearly differ in their genetic program from naturally occurring thymus-derived CD4+CD25+ TR cells. This distinct population of induced TR cells express neither CD25 nor the TR-associated transcription factor Foxp3. Strikingly, CD25 is not even up-regulated upon stimulation. Despite the lack in Foxp3 expression, these in vivo-induced CD25- TR cells are able to interfere with an Ag-specific CD8+ T cell-mediated intestinal inflammation without significant increase in CD25 and Foxp3 expression. Thus, our results demonstrate that in vivo-induced Ag-specific TR cells represent a distinct population of Foxp3-CD25- TR cells with regulatory capacity both in vitro and in vivo.
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Affiliation(s)
- Wiebke Hansen
- Institute of Medical Microbiology, University Hospital Essen, Essen, Germany.
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Sitohy B, Hammarström S, Danielsson A, Hammarström ML. Basal lymphoid aggregates in ulcerative colitis colon: a site for regulatory T cell action. Clin Exp Immunol 2008; 151:326-33. [PMID: 18190460 DOI: 10.1111/j.1365-2249.2007.03566.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Regulatory T cells seem to play a central role in maintaining immune tolerance in the gut mucosa. Previously we have shown that interleukin (IL)-10 is produced at high levels in the inflamed colonic tissue of ulcerative colitis (UC) patients. The cellular source was CD4+ T cells, suggesting local activation of regulatory T cells. The present study was performed to determine whether the frequency of regulatory T cells is increased in UC colon and whether they are present in the basal lymphoid aggregates, the prominent microanatomical structure in UC colon. Colonic tissue specimens from UC and control patients were analysed for frequencies of lamina propria lymphocytes expressing the regulatory T cell markers forkhead box protein 3 (FoxP3), CD25 and glucocorticoid-induced tumour necrosis factor receptor family-related gene (GITR) as well as CD28, CD4 and CD3 by using marker specific reagents in immunomorphometry. Two-colour immunohistochemistry was used for detection of CD25/IL-10, FoxP3/IL-10 and CD25/FoxP3 double-positive cells. GITR+ and FoxP3+ cells were present in normal colon mucosa, although at a relatively low frequency, and were located preferentially within the solitary follicles. UC was associated with significantly increased frequencies of CD25+, GITR+ and FoxP3+ lamina propria lymphocytes both within the basal lymphoid aggregates and in the lamina propria outside. Many of the CD25+ cells co-expressed FoxP3 as well as IL-10, suggesting that these are indeed IL-10 secreting regulatory T cells, activated in an attempt to counteract the inflammation. Increased frequency of regulatory T cell subtypes seems insufficient to control the disease activity in UC.
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Affiliation(s)
- B Sitohy
- Department of Clinical Microbiology, Immunology, Umeå Unviersity, Umeå, Sweden
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van Driel IR, Ang DKY, Konz RF, Senices M, Young DA, Grusby MJ, Collins M, Dunussi-Joannopoulos K. Role of regulatory T cells in gastrointestinal inflammatory disease. J Gastroenterol Hepatol 2008; 23:171-7. [PMID: 18289352 DOI: 10.1111/j.1440-1746.2007.05278.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Regulatory T cells curb unwanted immune responses and regulate responses to microflora and it is now clear that regulatory T cells play an important role in a number of chronic inflammatory diseases of the gut. First, regulatory T cells are crucial in controlling immune responses to gastric autoantigens and thus preventing autoimmune gastritis and pernicious anemia. Second, regulatory T cells may modulate the response to Helicobacter pylori, thus affecting the ability of the immune system to clear the pathogen and mediate damage to the gastric mucosa. Finally, regulatory T cells play an important role in preventing damaging inflammatory responses to commensal organisms in the lower gut, thus guarding against inflammatory bowel diseases. In the present review, we examine the actions of regulatory T cells in the gut and conclude that further understanding of regulatory T cell biology may lead to new therapeutic approaches to chronic gastrointestinal disease.
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Affiliation(s)
- Ian R van Driel
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.
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CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation–mediated apoptosis of effector CD4+ T cells. Nat Immunol 2007; 8:1353-62. [DOI: 10.1038/ni1536] [Citation(s) in RCA: 880] [Impact Index Per Article: 48.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2007] [Accepted: 10/15/2007] [Indexed: 02/07/2023]
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