TYPE 1 INTERFERONS ARE MAJOR REGULATORS OF HUMAN MUCOSAL-ASSOCIATED INVARIANT T CELLS FUNCTIONS.

Human Mucosal-Associated Invariant T (MAIT) cells represent a subset of CD8+ innate-like T cells found in blood, mucosae and liver. They display anti-bacterial functions, owing to the recognition of highly conserved microbial metabolites associated to the monomorphic MHC class-I like molecule MR1 (MHC-Related 1). Hence, MAIT cells may represent an important line of defense against various pathogens, mostly intracellular bacteria. MAIT cells activation is also regulated by cytokines and innate microbial signals, in particular by TLR8 ligands and the combination of IL12+18, which activate MAIT cells in the absence of TCR stimulation. We now describe the prominent role of type 1 IFN as major regulators of MAIT cells functions. In the absence of TCR signals, IFNalpha/beta activate MAIT cells, in synergy with the combination of IL-1beta and IL-12. More strikingly, IFNalpha very strongly potentiates TCR signaling in MAIT cells, in a manner that is not found in other CD8+ T cell subsets. MAIT cells respond poorly to anti-CD3 stimulation, but IFNalpha dramatically increases the number of IFNgamma-producing MAIT cells; a similar effect is observed on degranulation. IFNalpha acts directly on MAIT cells with STAT phosphorylation. The TLR agonists poly I:C and R848 also potentiate MAIT cells response to anti-CD3 stimulation in an IFNalpha-dependent manner. Finally, exogenous IFNalpha potentiates MAIT cells responses to heat-killed bacteria. Altogether, these results demonstrate that MAIT cells display a major and specific sensitivity to type 1 IFN, which is probably highly relevant to infections with intracellular bacteria but also in other chronic inflammatory disorders.