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Eur J Immunol. 2015 Aug;45(8):2286-98. doi: 10.1002/eji.201445313. Epub 2015 Jun 22.

IL-15 dependent induction of IL-18 secretion as a feedback mechanism controlling human MAIT-cell effector functions.

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Department of Immunology, Berlin-Brandenburg-Center for Regenerative Therapies (BCRT), Berlin, Germany.
Department of Nephrology and Internal Intensive Care, Charite University Hospital, Berlin, Germany.
Medical Clinic I, Marien Hospital Herne, Ruhr University Bochum, Germany.


Mucosal-associated invariant T (MAIT) cells are characterized by an invariant TCRVα7.2 chain recognizing microbial vitamin B metabolites presented by the MHC-Ib molecule MR1. They are mainly detectable in the CD8(+) and CD8(-) CD4(-) "double negative" T-cell compartments of mammals and exhibit both Th1- and Th17-associated features. As MAIT cells show a tissue-homing phenotype and operate at mucosal surfaces with myriads of pathogenic encounters, we wondered how IL-15, a multifaceted cytokine being part of the intestinal mucosal barrier, impacts on their functions. We demonstrate that in the absence of TCR cross-linking, human MAIT cells secrete IFN-γ, increase perforin expression and switch on granzyme B production in response to IL-15. As this mechanism was dependent on the presence of CD14(+) cells and sensitive to IL-18 blockade, we identified IL-15 induced IL-18 production by monocytes as an inflammatory, STAT5-dependent feedback mechanism predominantly activating the MAIT-cell population. IL-15 equally affects TCR-mediated MAIT-cell functions since it dramatically amplifies bacteria-induced IFN-γ secretion, granzyme production, and cytolytic activity at early time points, an effect being most pronounced under suboptimal TCR stimulation conditions. Our data reveal a new quality of IL-15 as player in an inflammatory cytokine network impacting on multiple MAIT-cell functions.


Cytokines; IL-15; Inflammation; MAIT-cells; T cells

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