Original Research ARTICLE
Clostridioides difficile activates human mucosal-associated invariant T cells
- 1Institut für Medizinische Mikrobiologie und Krankenhaushygiene, Medizinische Fakultät, Universitätsklinikum Magdeburg, Germany
- 2Molecular Structural Biology, Helmholtz-Zentrum für Infektionsforschung, Helmholtz-Gemeinschaft Deutscher Forschungszentren (HZ), Germany
- 3Internationale Graduiertenschule ABINEP, Otto von Guericke Universität Magdeburg, Germany
- 4Braunschweig Integrated Centre of Systems Biology (BRICS), Germany
- 5Fakultät Informatik, Hochschule für angewandte Wissenschaften, Germany
- 6Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ), Germany
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.
Keywords: C. difficile infection (CDI), MAIT cells, MR1-antigen presentation, riboflavin synthesis, mucosal immunity
Received: 13 Jul 2018;
Accepted: 04 Oct 2018.
Edited by:Alain P. Gobert, Vanderbilt University Medical Center, United States
Reviewed by:Mariolina Salio, University of Oxford, United Kingdom
Alexandra J. Corbett, The University of Melbourne, Australia
Copyright: © 2018 Bernal, Hofmann, Bulitta, Klawonn, Michel, Jahn, Neumann-Schaal, Bruder and Jänsch. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Prof. Dunja Bruder, Institut für Medizinische Mikrobiologie und Krankenhaushygiene, Medizinische Fakultät, Universitätsklinikum Magdeburg, Magdeburg, 39120, Saxony-Anhalt, Germany, email@example.com
Prof. Lothar Jänsch, Helmholtz-Zentrum für Infektionsforschung, Helmholtz-Gemeinschaft Deutscher Forschungszentren (HZ), Molecular Structural Biology, Braunschweig, 38124, Niedersachsen, Germany, Lothar.Jaensch@helmholtz-hzi.de