Hebbandi Nanjundappa, Roopa; Ronchi, Francesca; Wang, Jinguo; Clemente-Casares, Xavier; Yamanouchi, Jun; Sokke Umeshappa, Channakeshava; Yang, Yang; Blanco, Jesús; Bassolas-Molina, Helena; Salas, Azucena; Khan, Hamza; Slattery, Robyn M; Wyss, Madeleine; Mooser, Catherine; Macpherson, Andrew; Sycuro, Laura K; Serra, Pau; McKay, Derek M; McCoy, Kathleen and Santamaria, Pere (2017). A Gut Microbial Mimic that Hijacks Diabetogenic Autoreactivity to Suppress Colitis. Cell, 171(3), 655-667.e17. Cell Press 10.1016/j.cell.2017.09.022
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The gut microbiota contributes to the development of normal immunity but, when dysregulated, can promote autoimmunity through various non-antigen-specific effects on pathogenic and regulatory lymphocytes. Here, we show that an integrase expressed by several species of the gut microbial genus Bacteroides encodes a low-avidity mimotope of the pancreatic β cell autoantigen islet-specific glucose-6-phosphatase-catalytic-subunit-related protein (IGRP206-214). Studies in germ-free mice monocolonized with integrase-competent, integrase-deficient, and integrase-transgenic Bacteroides demonstrate that the microbial epitope promotes the recruitment of diabetogenic CD8+ T cells to the gut. There, these effectors suppress colitis by targeting microbial antigen-loaded, antigen-presenting cells in an integrin β7-, perforin-, and major histocompatibility complex class I-dependent manner. Like their murine counterparts, human peripheral blood T cells also recognize Bacteroides integrase. These data suggest that gut microbial antigen-specific cytotoxic T cells may have therapeutic value in inflammatory bowel disease and unearth molecular mimicry as a novel mechanism by which the gut microbiota can regulate normal immune homeostasis. PAPERCLIP.
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