Synergistic TCR-independent action of IL-33 and IL-12 drive a potent IFNγ secretory program in human circulating MAIT cells with immunomodulatory properties.

Introduction: Mucosal-Associated Invariant T (MAIT) cells are a subset of unconventional T cells that rapidly respond to early signs of inflammation, infection, and tissue damage. While MAIT cells have been typically associated with microbial infections, given their ability to respond to both microbial-derived riboflavin metabolites and proinflammatory cytokines such as IL-12, IL-15, or IL-18, their role in other inflammatory conditions remains mostly unknown. Alarmins, including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), are crucial effectors for early inflammatory responses, being released upon epithelial damage and strongly promoting the polarization of a wide variety of immune cells, including leukocytes like neutrophils, monocytes, macrophages, dendritic cells (DCs), NK cells, ILCs and T cells. However, how alarmins-induced environments influence MAIT cells' activity and function is yet to be explored. Methods: In this study, we investigate the roles of alarmins in controlling MAIT cell activation and function. Results: We found that IL-33, but not IL-25 or TSLP, combined with the TCR-independent stimuli IL-12p70 (but not 5-OP-RU), induces a potent IFNγ secretory/cytotoxic program on MAIT cells. This response was strongly dependent on p38 MAPK signaling and glycolytic metabolism. Beyond IFNγ, IL-33/IL-12p70-activated MAIT cells secrete a diverse panel of immune mediators, including TNF, VEGF, OSM, CXCL11, and CCL3. Notably, conditioned media from purified Vα7.2 Discussion: These findings reveal a broader immunomodulatory potential for MAIT cells to influence diverse immune compartments during inflammatory response.