title: IL-15 dependent induction of IL-18 secretion as a feedback mechanism controlling human MAIT-cell effector functions.
abstract: 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.
authors.affiliation: Department of Immunology, Berlin-Brandenburg-Center for Regenerative Therapies (BCRT), Berlin, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Sattler
authors.affiliation: Department of Immunology, Berlin-Brandenburg-Center for Regenerative Therapies (BCRT), Berlin, Germany.
authors.forename: Chantip
authors.initials: C
authors.lastname: Dang-Heine
authors.affiliation: Department of Immunology, Berlin-Brandenburg-Center for Regenerative Therapies (BCRT), Berlin, Germany.|Department of Nephrology and Internal Intensive Care, Charite University Hospital, Berlin, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Reinke
authors.affiliation: Department of Immunology, Berlin-Brandenburg-Center for Regenerative Therapies (BCRT), Berlin, Germany.|Medical Clinic I, Marien Hospital Herne, Ruhr University Bochum, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Babel
mesh_terms: D005260:Female; D006801:Humans; D007152:Immunologic Capping; D007371:Interferon-gamma / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000502:physiology*; D008297:Male; D009092:Mucous Membrane / Q000166:cytology / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
chemical_list: C573415:IFNG protein, human; C569274:IL15 protein, human; C000589760:IL18 protein, human; D019409:Interleukin-15; D020382:Interleukin-18; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma
keywords: Cytokines; IL-15; Inflammation; MAIT-cells; T cells