Human MAIT10 and MAIT17 profiles are effector states directed by the cytokine milieu

Mucosa-associated invariant T (MAIT) cells are unconventional MR1-restricted T cells with rapid innate-like response characteristics. MAIT cells can mediate broad effector functions, including bacterial cytolysis and production of a range of pro-inflammatory cytokines. However, how the MAIT cell antigen response profile is controlled is unclear. Incorporating functional and transcriptomic analyses we define three distinct MAIT cell effector programs driven by the cytokine milieu during antigen recognition. Activation by TCR signaling together with IL-12 or IL-23 drives a program biased towards IL-10 through the transcription factor c-MAF and the expression of the inhibitory receptors TIM-3, LAG-3 and PD-1 (MAIT10). Co-activation with IL-18 supports responses dominated by IL-17, GM-CSF, IFNγ and TNF (MAIT17). The IL-18-driven inflammatory and tissue-repair program vetoes IL-10 expression. On the contrary, TCR activation without cytokine co-activation drives primarily cytolytic arming. These activation states are transient and reflect the adaptation of MAIT cells to the local milieu. MAIT cell IL-10 production serves an autocrine regulatory function in addition to influence the state of monocytes. Finally, in active Crohn’s disease patients, the MAIT10 profile is suppressed. Together, these findings demonstrate that MAIT cells adapt their effector response programs to the local cytokine milieu.