Immune checkpoint expression in mucosal-associated invariant T cells is stimulus-dependent.

Mucosal-associated invariant T (MAIT) cells are unique unconventional T cells with diverse roles in immunity, yet how their context informs their function is not well known. This contextual regulation is particularly relevant in cancer, where MAIT cells have an enigmatic role. We performed a systematic review and meta-analysis to identify MAIT cell transcriptomic signatures under different environmental conditions. We identified 4 bulk-RNA-sequencing studies that compared multiple activation stimuli. We found a stimulus-specific transcriptional signature for immune checkpoint genes, that we confirmed in a single-cell RNA-sequencing dataset. We used flow cytometry to examine in vitro human MAIT cells across 4 activation stimuli and confirmed that stimulus drives unique checkpoint signatures upon MAIT activation for Lag3, PD-L1, PD-1, NKG2A, and Tigit. Strikingly, PD-L1 was more highly induced in vitro than PD-1 in MAIT cells up to 72 h. Our data suggest that human MAIT cell regulation is context-dependent. These findings have the potential to critically inform efforts targeting MAIT cells for cancer immunotherapy.