T-Cell Specificity Matters in IBD: Impaired IL10 Production Revealed by OmpC-Tetramers

Crohn’s disease (CD) is a is a chronic inflammatory disorder of the intestinal mucosa. Uncontrolled cycles of inflammation result in cumulative intestinal damage and there is an urgent need to find better ways to prevent or treat symptoms as early as possible. Effective intervention, however, requires knowledge of the triggers for disease onset and immune cells driving pathology. A key question in the study of CD, and indeed in inflammatory bowel disease (IBD) in general, has been: what are the antigens that drive this inappropriate immunity? In contrast to classic autoimmune diseases in which immune cells react inappropriately to self-antigens, accumulating evidence suggests that in IBD, the inappropriate response is to antigens from the intestinal microbiome. Early evidence from the seminal studies of Targan and Elson have shown that a significant proportion of CD patients have high levels of antibodies to bacterial flagellin proteins from Clostridium cluster XIVa (reviewed in1Alexander K.L. Targan S.R. Elson C.O. Microbiota activation and regulation of innate and adaptive immunity.Immunol Rev. 2014; 260: 206-220Crossref PubMed Scopus (89) Google Scholar). In support of the concept that bacterial antigens drive IBD, there are associations between the frequency and phenotype of bacterial-specific CD4+ T cells and IBD disease severity.2Calderon-Gomez E. Bassolas-Molina H. Mora-Buch R. Dotti I. Planell N. Esteller M. Gallego M. Marti M. Garcia-Martin C. Martinez-Torro C. Ordas I. Singh S. Panes J. Benitez-Ribas D. Salas A. Commensal-specific CD4(+) cells from patients with Crohn’s disease have a T-helper 17 inflammatory profile.Gastroenterology. 2016; 151: 489-500 e3Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 3Cook L. Lisko D.J. Wong M.Q. Garcia R.V. Himmel M.E. Seidman E.G. Bressler B. Levings M.K. Steiner T.S. Analysis of flagellin-specific adaptive immunity reveals links to dysbiosis in patients with inflammatory bowel disease.Cell Mol Gastroenterol Hepatol. 2020; 9: 485-506Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 4Hegazy A.N. West N.R. Stubbington M.J.T. Wendt E. Suijker K.I.M. Datsi A. This S. Danne C. Campion S. Duncan S.H. Owens B.M.J. Uhlig H.H. McMichael A. Oxford I.B.D.C.I. Bergthaler A. Teichmann S.A. Keshav S. Powrie F. Circulating and tissue-resident CD4(+) T cells with reactivity to intestinal microbiota are abundant in healthy individuals and function is altered during inflammation.Gastroenterology. 2017; 153: 1320-1337 e16Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar However, a limitation of these studies was that specific epitopes were not mapped, meaning that it was not possible to create tetramer reagents, mainstay reagents in the immunology tool box, which allow precise quantification and phenotypic characterization of antigen-specific T cells. Seeking to overcome this limitation, Uchida et al5Uchida A.M. Boden E.K. James E.A. Shows D.M. Konecny A.J. Lord J.D. Escherichia coli-specific CD4+ T cells have public T-cell receptors and low interleukin 10 production in Crohn's disease.Cell Mol Gastroenterol Hepatol. 2020; 10: 507-526Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar used tetramer-guided mapping to identify T-cell epitopes within the Escherichia coli outer-membrane porin C (OmpC), an antigen previously associated with perforating disease in CD patients.6Mow W.S. Vasiliauskas E.A. Lin Y.C. Fleshner P.R. Papadakis K.A. Taylor K.D. Landers C.J. Abreu-Martin M.T. Rotter J.I. Yang H. Targan S.R. Association of antibody responses to microbial antigens and complications of small bowel Crohn’s disease.Gastroenterology. 2004; 126: 414-424Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar They elected to focus on HLA-DRB1∗15:01–restricted epitopes because there was a high frequency of this HLA type in their cohort of individuals with OmpC-specific antibodies. They subsequently identified an HLA-DRB1∗15:01–restricted OmpC epitope, OmpC321–340, enabling tetramer-based analysis of antigen-specific CD4+ T cells. Consistent with previous reports2Calderon-Gomez E. Bassolas-Molina H. Mora-Buch R. Dotti I. Planell N. Esteller M. Gallego M. Marti M. Garcia-Martin C. Martinez-Torro C. Ordas I. Singh S. Panes J. Benitez-Ribas D. Salas A. Commensal-specific CD4(+) cells from patients with Crohn’s disease have a T-helper 17 inflammatory profile.Gastroenterology. 2016; 151: 489-500 e3Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 3Cook L. Lisko D.J. Wong M.Q. Garcia R.V. Himmel M.E. Seidman E.G. Bressler B. Levings M.K. Steiner T.S. Analysis of flagellin-specific adaptive immunity reveals links to dysbiosis in patients with inflammatory bowel disease.Cell Mol Gastroenterol Hepatol. 2020; 9: 485-506Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 4Hegazy A.N. West N.R. Stubbington M.J.T. Wendt E. Suijker K.I.M. Datsi A. This S. Danne C. Campion S. Duncan S.H. Owens B.M.J. Uhlig H.H. McMichael A. Oxford I.B.D.C.I. Bergthaler A. Teichmann S.A. Keshav S. Powrie F. Circulating and tissue-resident CD4(+) T cells with reactivity to intestinal microbiota are abundant in healthy individuals and function is altered during inflammation.Gastroenterology. 2017; 153: 1320-1337 e16Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar of bacterial-specific T cells in IBD, Uchida et al5Uchida A.M. Boden E.K. James E.A. Shows D.M. Konecny A.J. Lord J.D. Escherichia coli-specific CD4+ T cells have public T-cell receptors and low interleukin 10 production in Crohn's disease.Cell Mol Gastroenterol Hepatol. 2020; 10: 507-526Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar found that there was no difference between healthy controls and CD patients in the absolute number of circulating OmpC321–340–specific CD4+ T cells. In addition, as previously observed,2Calderon-Gomez E. Bassolas-Molina H. Mora-Buch R. Dotti I. Planell N. Esteller M. Gallego M. Marti M. Garcia-Martin C. Martinez-Torro C. Ordas I. Singh S. Panes J. Benitez-Ribas D. Salas A. Commensal-specific CD4(+) cells from patients with Crohn’s disease have a T-helper 17 inflammatory profile.Gastroenterology. 2016; 151: 489-500 e3Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar,3Cook L. Lisko D.J. Wong M.Q. Garcia R.V. Himmel M.E. Seidman E.G. Bressler B. Levings M.K. Steiner T.S. Analysis of flagellin-specific adaptive immunity reveals links to dysbiosis in patients with inflammatory bowel disease.Cell Mol Gastroenterol Hepatol. 2020; 9: 485-506Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar OmpC321–340–specific CD4+ T cells had a T-helper 17 cell phenotype, defined as CD161+CXCR3neg. After sorting and clonal expansion, tetramer+ OmpC321–340–specific cells retained antigen specificity and, strikingly, clones from CD patients secreted significantly less interleukin (IL)10 than those from healthy controls. Although not significant, there also was reduced production of the T-helper 2 cell cytokines IL4, IL5, and IL13, with no changes seen for IL2, IL6, IL13, IL21, tumor necrosis factor, or interferon γ, illustrating the restricted nature of the IL10-specific effect in CD patients. Moreover, blocking activation of the costimulatory receptor CD226 further enhanced IL10 expression by OmpC321–340–specific T cells from healthy controls, but not CD patients. T-cell–receptor sequencing of OmpC321–340–specific CD4+ T-cell clones showed that although the OmpC321–340–specific clones were polyclonal, they contained a substantial number of public clonotypes (ie, clonotypes with identical CDR3 amino acid sequences in several individuals). These data suggest that the majority of individuals have OmpC321–340 specific T cells and thus that immune responses to this epitope are not inherently pathogenic but rather that in CD the normal function of these cells is altered. This study advances our understanding of T-cell immunity in CD in several ways. First, it provides a tetramer reagent to study antigen-specific CD4+ T cells in this disease; an important technical advance. Second, it highlights important commonalities between CD and other autoimmune diseases, in which there is similar evidence for functional rather than numeric changes in self-reactive T cells. For example, in type 1 diabetes, most people have islet-reactive T cells, and protection from disease is associated with increased frequencies of islet-specific IL10-producing effector T cells and Forkhead Box protein 3+ regulatory T cells.7Wen X. Yang J. James E. Chow I.T. Reijonen H. Kwok W.W. Increased islet antigen-specific regulatory and effector CD4+ T cells in healthy individuals with the type 1 diabetes-protective haplotype.Sci Immunol Epub ahead of print February 14,. 2020; https://doi.org/10.1126/sciimmunol.aax8767Crossref Scopus (12) Google Scholar Third, it shows the T cell immunoreceptor with Ig and ITIM domains (TIGIT)/CD226 axis may be important in regulating IL10 production in human CD4+ T cells, providing new possibilities for therapeutic manipulation of IL10. Finally, together with recent literature, it solidifies the notion that the development of inappropriate adaptive immunity to intestinal bacterial is a key aspect of the pathogenesis of CD. Future studies should address why this specific reduction in IL10 secretion occurs and confirm the mechanistic basis. Defective IL10 secretion in cells after in vitro expansion suggests stable epigenetic changes. Understanding how these changes could be reversed will be an important step toward identifying new therapies for CD. Escherichia coli–Specific CD4+ T Cells Have Public T-Cell Receptors and Low Interleukin 10 Production in Crohn’s DiseaseCellular and Molecular Gastroenterology and HepatologyVol. 10Issue 3PreviewCrohn’s disease (CD) likely represents decreased immune tolerance to intestinal bacterial antigens. Most CD patients have high titers of antibodies to intestinal commensal proteins, including the outer membrane porin C (OmpC) of Escherichia coli. Full-Text PDF Open Access

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