IL-23 tunes inflammatory functions of human MAIT cells

IL-23 signaling plays a key role in the pathogenesis of chronic inflammatory and infectious diseases, yet the cellular targets and signaling pathways affected by this cytokine remain poorly understood. We show that IL-23 receptors are expressed on the large majority of human MAIT, but not of conventional T cells, suggesting that these innate-like T cells are critical mediators of IL-23 functions. In this study, we investigated the effects of IL-23 on human MAIT cell transcriptional and chromatin accessibility profiles, using RNA- and CITE-seq and ATAC-seq, respectively. Protein and transcriptional profiling at the population and single cell level demonstrates that stimulation with IL-23 or the structurally related cytokine IL-12 drives distinct functional profiles, revealing a high level of plasticity of MAIT cells. IL-23, in particular, affects key molecules and pathways related to autoimmunity and cytotoxic functions. Integrated analysis of transcriptomic and chromatin accessibility shows that AP-1 transcription factors constitute a key regulatory node of the IL-23 pathway in MAIT cells.