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      Peyer's patches-derived CD11b+ B cells recruit regulatory T cells through CXCL9 in dextran sulphate sodium-induced colitis

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          Abstract

          <p id="d116702e359">Regulatory T (Treg) cells play an essential role in the maintenance of intestinal homeostasis. In Peyer's patches (PPs), which comprise the most important IgA induction site in the gut‐associated lymphoid tissue, Treg cells promote IgA isotype switching. However, the mechanisms underlying their entry into PPs and isotype switching facilitation in activated B cells remain unknown. This study, based on the dextran sulphate sodium (DSS)‐induced colitis model, revealed that Treg cells are significantly increased in PPs, along with CD11b <sup>+</sup> B‐cell induction. Immunofluorescence staining showed that infiltrated Treg cells were located around CD11b <sup>+</sup> B cells and produced transforming growth factor‐ <i>β</i>, thereby inducing IgA <sup>+</sup> B cells. Furthermore, <i>in vivo</i> and <i>in vitro</i> studies revealed that CD11b <sup>+</sup> B cells in PPs had the capacity to recruit Treg cells into PPs rather than promoting their proliferation. Finally, we found that Treg cell recruitment was mediated by the chemokine CXCL9 derived from CD11b <sup>+</sup> B cells in PPs. These findings demonstrate that CD11b <sup>+</sup> B cells induced in PPs during colitis actively recruit Treg cells to accomplish IgA isotype switch in a CXCL9‐dependent manner. </p>

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          Chemically induced mouse models of intestinal inflammation.

          Animal models of intestinal inflammation are indispensable for our understanding of the pathogenesis of Crohn disease and ulcerative colitis, the two major forms of inflammatory bowel disease in humans. Here, we provide protocols for establishing murine 2,4,6-trinitro benzene sulfonic acid (TNBS)-, oxazolone- and both acute and chronic dextran sodium sulfate (DSS) colitis, the most widely used chemically induced models of intestinal inflammation. In the former two models, colitis is induced by intrarectal administration of the covalently reactive reagents TNBS/oxazolone, which are believed to induce a T-cell-mediated response against hapten-modified autologous proteins/luminal antigens. In the DSS model, mice are subjected several days to drinking water supplemented with DSS, which seems to be directly toxic to colonic epithelial cells of the basal crypts. The procedures for the hapten models of colitis and acute DSS colitis can be accomplished in about 2 weeks but the protocol for chronic DSS colitis takes about 2 months.
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            T-bet controls regulatory T cell homeostasis and function during type-1 inflammation

            Several subsets of Foxp3+ regulatory T (Treg) cells work in concert to maintain immune homeostasis. However, the molecular bases underlying the phenotypic and functional diversity of Treg cells remain obscure. We show that in response to interferon-γ, Foxp3+ Treg cells upregulated the T helper 1 (TH1)-specifying transcription factor T-bet. T-bet promoted expression of the chemokine receptor CXCR3 on Treg cells, and T-bet+ Treg cells accumulated at sites of TH1-mediated inflammation. Furthermore, T-bet expression was required for the homeostasis and function of Treg cells during type-1 inflammation. Thus, within a subset of CD4+ T cells, the activities of Foxp3 and T-bet are overlaid, resulting in Treg cells with unique homeostatic and migratory properties optimized for suppression of TH1 responses in vivo.
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              The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions.

              T cells infiltrating inflammatory sites are usually of the activated/memory type. The precise mechanism for the positioning of these cells within tissues is unclear. Adhesion molecules certainly play a role; however, the intricate control of cell migration appears to be mediated by numerous chemokines and their receptors. Particularly important chemokines for activated/memory T cells are the CXCR3 ligands IP-10 and Mig and the CCR5 ligands RANTES, macrophage inflammatory protein-1alpha, and macrophage inflammatory protein-1beta. We raised anti-CXCR3 mAbs and were able to detect high levels of CXCR3 expression on activated T cells. Surprisingly, a proportion of circulating blood T cells, B cells, and natural killer cells also expressed CXCR3. CCR5 showed a similar expression pattern as CXCR3, but was expressed on fewer circulating T cells. Blood T cells expressing CXCR3 (and CCR5) were mostly CD45RO+, and generally expressed high levels of beta1 integrins. This phenotype resembled that of T cells infiltrating inflammatory lesions. Immunostaining of T cells in rheumatoid arthritis synovial fluid confirmed that virtually all such T cells expressed CXCR3 and approximately 80% expressed CCR5, representing high enrichment over levels of CXCR3+ and CCR5+ T cells in blood, 35 and 15%, respectively. Analysis by immunohistochemistry of various inflamed tissues gave comparable findings in that virtually all T cells within the lesions expressed CXCR3, particularly in perivascular regions, whereas far fewer T cells within normal lymph nodes expressed CXCR3 or CCR5. These results demonstrate that the chemokine receptor CXCR3 and CCR5 are markers for T cells associated with certain inflammatory reactions, particularly TH-1 type reactions. Moreover, CXCR3 and CCR5 appear to identify subsets of T cells in blood with a predilection for homing to these sites.
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                Author and article information

                Journal
                Immunology
                Immunology
                Wiley
                00192805
                November 2018
                November 2018
                July 26 2018
                : 155
                : 3
                : 356-366
                Affiliations
                [1 ]Department of Immunology; School of Basic Medical Sciences; Institute of Biomedical Sciences; Fudan University; Shanghai China
                [2 ]Department of Pathology; The University of Hong Kong; Hong Kong China
                [3 ]Northfield Mount Hermon School; Mount Hermon MA USA
                [4 ]Biotherapy Research Centre; Fudan University; Shanghai China
                Article
                10.1111/imm.12977
                6187209
                29969845
                3caca60c-0819-4013-9c58-9f32662c8c18
                © 2018

                http://doi.wiley.com/10.1002/tdm_license_1.1

                http://onlinelibrary.wiley.com/termsAndConditions#vor

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