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MAdCAM costimulation through Integrin-?4?7 promotes HIV replication.

ABSTRACT: Human gut-associated lymphoid tissues (GALT) play a key role in the acute phase of HIV infection. The propensity of HIV to replicate in these tissues, however, is not fully understood. Access and migration of naive and memory CD4+ T cells to these sites is mediated by interactions between integrin ?4?7, expressed on CD4+ T cells, and MAdCAM, expressed on high endothelial venules. We report here that MAdCAM delivers a potent costimulatory signal to naive and memory CD4+ T cells following ligation with ?4?7. Such costimulation promotes high levels of HIV replication. An anti-?4?7 mAb that prevents mucosal transmission of SIV blocks MAdCAM signaling through ?4?7 and MAdCAM-dependent viral replication. MAdCAM costimulation of memory CD4+ T cells is sufficient to drive cellular proliferation and the upregulation of CCR5, while naive CD4+ T cells require both MAdCAM and retinoic acid to achieve the same response. The pairing of MAdCAM and retinoic acid is unique to the GALT, leading us to propose that HIV replication in these sites is facilitated by MAdCAM-?4?7 interactions. Moreover, complete inhibition of MAdCAM signaling by an anti-?4?7 mAb, an analog of the clinically approved therapeutic vedolizumab, highlights the potential of such agents to control acute HIV infection.

SUBMITTER: Nawaz F

PROVIDER: S-EPMC6160318 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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MAdCAM costimulation through Integrin-α4β7 promotes HIV replication.

Nawaz Fatima F Goes Livia R LR Ray Jocelyn C JC Olowojesiku Ronke R Sajani Alia A Ansari Aftab A AA Perrone Ian I Hiatt Joseph J Van Ryk Donald D Wei Danlan D Waliszewski Mia M Soares Marcelo A MA Jelicic Katija K Connors Mark M Migueles Stephen A SA Martinelli Elena E Villinger Francois F Cicala Claudia C Fauci Anthony S AS Arthos James J

Mucosal immunology 20180606 5

Human gut-associated lymphoid tissues (GALT) play a key role in the acute phase of HIV infection. The propensity of HIV to replicate in these tissues, however, is not fully understood. Access and migration of naive and memory CD4+ T cells to these sites is mediated by interactions between integrin α4β7, expressed on CD4+ T cells, and MAdCAM, expressed on high endothelial venules. We report here that MAdCAM delivers a potent costimulatory signal to naiv ...[more]

PMID: 29875402

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Project description:Background & aimsAberrant lymphocyte homing could potentially link inflammatory processes in the intestine and the liver, as distinct hepatobiliary diseases frequently develop as extra-intestinal manifestations in inflammatory bowel disease. In this study, we examined the role of the gut-tropic leukocyte adhesion molecule β7 integrin and its endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) in immune-mediated hepatitis in mice.MethodsWild-type (WT) mice, MAdCAM-1-deficient mice, β7 integrin-deficient mice, RAG-2-deficient mice, RAG-2/MAdCAM-1 double-deficient mice, and RAG-2/β7 integrin double-deficient mice were subjected to concanavalin A (ConA)-induced hepatitis. The degree of hepatitis was evaluated by histology, flow cytometry, and expression analysis of inflammatory mediators. The motility of lymphocytes in progressive liver damage was assessed by intravital laser scanning multiphoton microscopy.ResultsAblation of MAdCAM-1 or β7 integrin ameliorated ConA-induced hepatitis in mice. β7 integrin-deficient lymphocytes caused less liver damage than WT lymphocytes in ConA-treated RAG-2-deficient mice. Moreover, WT lymphocytes caused less liver damage in ConA-treated RAG-2/β7 integrin double-deficient mice than in similarly treated RAG-2-deficient mice, indicating that β7 integrin expression contributes significantly to the liver damage mediated by innate immune cells. MAdCAM-1 expression was dependent on β7 integrin expression on adaptive and innate immune cells. Most importantly, lymphocytes in ConA-treated MAdCAM-1-deficient mice displayed more motility and less adhesion in the liver sinusoids in vivo, than lymphocytes in similarly treated WT mice.ConclusionsThese data suggest that β7 integrin expression on lymphocytes and innate immune cells contributes to MAdCAM-1 upregulation and liver damage in acute immune-mediated hepatitis, most likely by facilitating lymphocyte/sinusoidal endothelial cell interactions.

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MAdCAM costimulation through Integrin-?4?7 promotes HIV replication.

Publications

MAdCAM costimulation through Integrin-α<sub>4</sub>β<sub>7</sub> promotes HIV replication.

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