TY - JOUR AU - Bernal, Isabel AU - Hofmann, Julia Danielle AU - Bulitta, Björn AU - Klawonn, Frank AU - Michel, Annika-Marisa AU - Jahn, Dieter AU - Neumann-Schaal, Meina AU - Bruder, Dunja AU - Jänsch, Lothar PY - 2018 M3 - Original Research TI - Clostridioides difficile Activates Human Mucosal-Associated Invariant T Cells JO - Frontiers in Microbiology UR - https://www.frontiersin.org/articles/10.3389/fmicb.2018.02532 VL - 9 SN - 1664-302X N2 - Clostridioides difficile infection (CDI) causes severe inflammatory responses at the intestinal mucosa but the immunological mechanisms underlying CDI-related immunopathology are still incompletely characterized. Here we identified for the first time that both, non-toxigenic strains as well as the hypervirulent ribotypes RT027 and RT023 of Clostridioides difficile (formerly Clostridium difficile), induced an effector phenotype in mucosal-associated invariant T (MAIT) cells. MAIT cells can directly respond to bacterial infections by recognizing MR1-presented metabolites derived from the riboflavin synthesis pathway constituting a novel class of antigens. We confirmed functional riboflavin synthesis of C. difficile and found fixed bacteria capable of activating primary human MAIT cells in a dose-dependent manner. C. difficile-activated MAIT cells showed an increased and MR1-dependent expression of CD69, proinflammatory IFNγ, and the lytic granule components granzyme B and perforin. Effector protein expression was accompanied by the release of lytic granules, which, in contrast to other effector functions, was mainly induced by IL-12 and IL-18. Notably, this study revealed hypervirulent C. difficile strains to be most competent in provoking MAIT cell responses suggesting MAIT cell activation to be instrumental for the immunopathology observed in C. difficile-associated colitis. In conclusion, we provide first evidence for a link between C. difficile metabolism and innate T cell-mediated immunity in humans. ER -