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      β7 Integrin Inhibition Can Increase Intestinal Inflammation by Impairing Homing of CD25 hiFoxP3 + Regulatory T Cells

      research-article
      1 , 1 , 2 , 1 , 3 , 1 ,
      Cellular and Molecular Gastroenterology and Hepatology
      Elsevier
      Integrin β7 Blockade, Inflammatory Bowel Disease, Regulatory T Cells, Gut-Associated Lymphoid Tissue, CD, Crohn’s disease, CFSE, carboxyfluorescein succinimidyl ester, DSS, dextran sodium sulfate, GALT, gut-associated lymphoid tissue, GFP, green fluorescent protein, IBD, inflammatory bowel disease, ITGB, Integrin subunit beta, IL, interleukin, MAdCAM-1, mucosal addressin cell adhesion molecule-1, MLN, mesenteric lymph node, PCR, polymerase chain reaction, PLN, peripheral lymph node, PP, Peyer’s patch, SP, spleen, Tconv, conventional T cells, TGF, transforming growth factor, Th, helper T cell, Treg, regulatory T cell, UC, ulcerative colitis, WT, wild-type

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          Abstract

          Background & Aims

          Integrin α4β7 mediates lymphocyte trafficking to the gut and gut-associated lymphoid tissues, a process critical for recruitment of effector lymphocytes from the circulation to the gut mucosa in inflammatory bowel disease (IBD) and murine models of intestinal inflammation. Antibody blockade of β7 integrins generally is efficacious in IBD; however, some patients fail to respond, and a few patients can experience exacerbations. This study examined the effects of loss of β7 integrin function in murine models of IBD.

          Methods

          In a mouse IBD model caused by lack of interleukin 10, a cytokine important in CD25 hiFoxP3 + regulatory T cell (Treg) function, genetic deletion of β7 integrin or antibody blockade of α4β7–mucosal addressin cell adhesion molecule-1 interaction paradoxically exacerbated colitis.

          Results

          Loss of β7 impaired the capacity of Tregs homing to the gut and therefore suppress intestinal inflammation in an adoptive T-cell transfer model; however, the intrinsic suppressive function of β7-deficient Tregs remained intact, indicating that the β7 deficiency selectively impacts gut homing. Deletion of β7 integrin did not worsen colitis in an acute dextran sodium sulfate model in which Treg number and function were normal.

          Conclusions

          In Integrin subunit beta ( Itgb) 7 -/- Il10 -/- mice, loss of β7-dependent Treg homing to gut-associated lymphoid tissues combined with loss of intrinsic Treg function exacerbated intestinal inflammation. These results suggest that IBD patients with reduced CD25 hiFoxP3 + Treg numbers or function or lack of interleukin 10 could be at risk for failure of α4β7 blocking therapy.

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          Most cited references34

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          The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis.

          Decreased expression of the Nlrp3 protein is associated with susceptibility to Crohn's disease. However, the role of Nlrp3 in colitis has not been characterized. Nlrp3 interacts with the adaptor protein ASC to activate caspase-1 in inflammasomes, which are protein complexes responsible for the maturation and secretion of interleukin-1beta (IL-1beta) and IL-18. Here, we showed that mice deficient for Nlrp3 or ASC and caspase-1 were highly susceptible to dextran sodium sulfate (DSS)-induced colitis. Defective inflammasome activation led to loss of epithelial integrity, resulting in systemic dispersion of commensal bacteria, massive leukocyte infiltration, and increased chemokine production in the colon. This process was a consequence of a decrease in IL-18 in mice lacking components of the Nlrp3 inflammasome, resulting in higher mortality rates. Thus, the Nlrp3 inflammasome is critically involved in the maintenance of intestinal homeostasis and protection against colitis.
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            Current and emerging therapeutic targets for IBD

            The management of IBD has undergone major advances with the development of biologic agents. Here, Markus Neurath provides an overview of current and future therapeutic targets for IBD, including insights into the mechanisms and rationale behind such approaches.
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              Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3- precursor cells in the absence of interleukin 10.

              CD4(+) regulatory T cells (T(reg) cells) that produce interleukin 10 (IL-10) are important contributors to immune homeostasis. We generated mice with a 'dual-reporter' system of the genes encoding IL-10 and the transcription factor Foxp3 to track T(reg) subsets based on coordinate or differential expression of these genes. Secondary lymphoid tissues, lung and liver had enrichment of Foxp3(+)IL-10(-) T(reg) cells, whereas the large and small intestine had enrichment of Foxp3(+)IL-10(+) and Foxp3(-)IL-10(+) T(reg) cells, respectively. Although negative for Il10 expression, both Foxp3(+) and Foxp3(-) CD4(+) thymic precursor cells gave rise to peripheral IL-10(+) T(reg) cells, with only Foxp3(-) precursor cells giving rise to all T(reg) subsets. Each T(reg) subset developed in IL-10-deficient mice, but this was blocked by treatment with antibody to transforming growth factor-beta. Thus, Foxp3(+) and Foxp3(-) precursor cells give rise to peripheral IL-10-expressing T(reg) cells by a mechanism dependent on transforming growth factor-beta and independent of IL-10.
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                Author and article information

                Contributors
                Journal
                Cell Mol Gastroenterol Hepatol
                Cell Mol Gastroenterol Hepatol
                Cellular and Molecular Gastroenterology and Hepatology
                Elsevier
                2352-345X
                2020
                09 November 2019
                : 9
                : 3
                : 369-385
                Affiliations
                [2 ]Inflammatory Bowel Disease Center, University of California San Diego, La Jolla, California
                [3 ]Division of Gastroenterology, University of California San Diego, La Jolla, California
                [1 ]Department of Medicine, University of California San Diego, La Jolla, California
                Author notes
                [] Correspondence Address correspondence to: Mark H. Ginsberg, MD, Department of Medicine, University of California San Diego, 9500 Gilman Drive, MC 0726, La Jolla, California 92096. mhginsberg@ 123456ucsd.edu
                Article
                S2352-345X(19)30148-1
                10.1016/j.jcmgh.2019.10.012
                7016000
                31707128
                adc420b0-a7c9-4004-87a2-07f84b9a96d9
                © 2020 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 5 July 2019
                : 30 October 2019
                Categories
                Original Research

                integrin β7 blockade,inflammatory bowel disease,regulatory t cells,gut-associated lymphoid tissue,cd, crohn’s disease,cfse, carboxyfluorescein succinimidyl ester,dss, dextran sodium sulfate,galt, gut-associated lymphoid tissue,gfp, green fluorescent protein,ibd, inflammatory bowel disease,itgb, integrin subunit beta,il, interleukin,madcam-1, mucosal addressin cell adhesion molecule-1,mln, mesenteric lymph node,pcr, polymerase chain reaction,pln, peripheral lymph node,pp, peyer’s patch,sp, spleen,tconv, conventional t cells,tgf, transforming growth factor,th, helper t cell,treg, regulatory t cell,uc, ulcerative colitis,wt, wild-type

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