MiR-17-92 regulates MAIT cell development and function

Abstract

Abstract Mucosal-associated invariant T (MAIT) cells are innate-like T cells that acquire an effector function and differentiate into MAIT1 (T-bet+) and MAIT17 (RORγt+) subsets prior to thymic export. Upon activation, MAIT cells quickly release IFN-γ and IL-17, which modulate a broad spectrum of diseases, including autoimmunity, infection, allergy and cancer. miRNAs are no-coding RNAs regulating immune cell development and function. A recent study indicated defective MAIT cell development in the miRNAs-deficient mice, but, the specific miRNAs that guide their development remain unclear. Previous studies indicated that miR-17-92 regulates different immune cell development and function, however, the role of miR-17-92 in the MAIT cell development remains unclear. Here, we generated T cell specific miR-17-92 knockout (KO) mice to test the role of miR-17-92 in MAIT cell development and function. We found that deletion of miR-17-92 led to a profound defect on the MAIT cells in the number and frequencies in the thymus and peripheral immune organs, including spleen, lymph nodes, and liver, as well as in the lung and peritoneal cavity (P<0.05). The frequency of MAIT17 cells was dramatically reduced in miR-17-92 KO mice, while the frequency of MAIT1 cells was dramatically increased in thymic and peripheral immune organs, compared to wild-type (WT) controls. Furthermore, upon PMA/Ionomycin stimulation, we found a defect of IL-17 production, with significantly increased IFN-γ production by peripheral MAIT cells in miR-17-92 KO mice, compared to WT controls. The detailed miR-17-92 targeting pathway by RNA-Seq and Chip-Seq is under the investigation. Overall, our data indicated that miR-17-92 plays a pivotal role in MAIT cell development and function.