To Örebro University

Mucosal-associated invariant T (MAIT) cells are unconventional MR1-restricted T cells mediating rapid innate-like antimicrobial immunity. However, how the functional heterogeneity of human MAIT cell responses is controlled is largely unclear. Here, combining functional and transcriptomic analyses we define distinct MAIT cell effector programs directed by the cytokine milieu during antigen recognition. Activation by TCR signaling together with IL-12 or IL-23 drives c-MAF-dependent IL-10 production, with intermediate levels of IFNγ/TNF, and elevated expression of TIM-3, LAG-3, and PD-1. The MAIT-derived IL-10 mediates both autocrine and paracrine immune regulation. In active Crohn’s disease, the MAIT cell IL-10 regulatory profile appears to be suppressed. In contrast to the action of IL-12, co-activation of MAIT cells with IL-18 strongly co-activates IL-17, GM-CSF, IFNγ and TNF, while counteracting IL-10 expression. Finally, TCR activation without cytokine co-activation drives primarily cytolytic arming. These activation states are transient and do not represent stable subsets. Altogether, these findings demonstrate how cytokine cues direct transient MAIT cell effector response programs.