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.Keywords: Cytokines r IL-15 r Inflammation r MAIT-cells r T cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMucosal-associated invariant T cells (MAIT) comprise a sizable subset within the CD8 + and CD8 − CD4 − "double negative"(DN) T-cell compartment of mammals that is gaining increasing [7]. Diminished frequencies of MAIT cells in peripheral blood, accompanied by an enrichment in lungs and ascites of tuberculosis-infected individuals [5], indirectly support a role in host defense that is substantiated by various murine infection models [8][9][10][11]. Recent studies suggest that MAIT cells might also contribute to chronic inflammation being detectable in tissue lesions of patients suffering from inflammatory bowel disease [12], psoriasis [13], and multiple sclerosis [14]. The precise mechanisms by which MAIT cells exert their effector functions are still incompletely understood. MAIT cells exhibit a molecular "Th1+17" pattern and share phenotypic and functional features with both Th-cell lineages. Accordingly, IFN-γ, TNF-α, and IL-17 are the signature cytokines induced upon activation [4], along with constitutive expression of receptors for the cytokines IL-23, 15]. As for conventional T cells, ligation of these molecules not only governs primary differentiation in concert with TCR stimulation, but in part also initiates effector functions in effector/memory-type cells in a TCR-independent manner. In that context, we previously demonstrated that proinflammatory mediators, with the IL-2R γ-chain signaling cytokine IL-15 being indispensable, trigger IFN-γ release...

Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18–dependent activation

“…+ T cells at multiple time points after disease onset: days 6-12, days 13-20, and days [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] (Fig. 1B).…”

The role of mucosal‐associated invariant T cells in infectious diseases

“…10,[16][17][18][19] MAIT cell activation can result from either TCR-dependent signalling (triggered by ligand presented on MR1 by antigen-presenting cells) or from TCR-independent cytokine signalling. [20][21][22][23] Like other 'innate-like' lymphocytes including invariant natural killer T ª 2016 John Wiley & Sons Ltd, Immunology, 150, [45][46][47][48][49][50][51][52][53][54] cells and natural killer cells, MAIT cells respond rapidly to activation by producing cytokines and cytolytic products. Upon TCR-dependent or TCR-independent activation, MAIT cells produce interferon-c (IFN-c), tumour necrosis factor-a (TNF-a), cytolytic products (perforin, granulysin and granzymes) and degranulate (exposing CD107a to the cell surface).…”

“…22 Both IL-15 and IL-7 have each been shown to license MAIT cells for enhanced production of TCR-activated proinflammatory cytokines and cytolytic products. 23,26,27 MAIT cells express the transcription factors promyelocytic leukaemia zinc finger protein (PLZF) and RAR-related orphan receptor (RORcs) and do not develop in Rorc À/À mice. 26,28 Multiple groups have noted that circulating MAIT cells produce IL-17 upon PMA/ionomycin stimulation but not TCR-triggered stimulation.…”

“…13,20,33 The production of cytokines and cytolytic products by MAIT cells in these experiments appears to largely depend on TCR signalling triggered by MR1-presented ligand and can be augmented by pre-conditioning with a number of cytokines including IL-12, IL-23, IL-15 and IL-7. 22,23,26,27 Adding MAIT cells to infected cells can result in lysis or apoptosis of the infected cells. 1,25,26 Moreover, MAIT cells have the ability to decrease mycobacterial burden when added to experimentally infected cell cultures.…”

The role of human CD1c+ DCs at activating innate and adaptive immune responses

“…MAIT cells recognise vitamin B metabolites which are presented in the context of the MR1 molecule (Huang et al, 2008). MAIT cells are known to react towards IL-12p70 and IL-23 leading to the production of IFN-γ and IL-17A, respectively (Sattler et al, 2015, Ussher et al, 2014, Cho et al, 2014. The role of human DCs at activating MAIT cells remains to be determined.…”