MicroRNA-155 regulates MAIT cell development, effector subsets differentiation and function

Abstract

Abstract Mucosal-associated invariant T (MAIT) cells are innate-like T cells that develop in the thymus through sequential maturation stages and differentiate into MAIT1 (T-bet+) and MAIT17 (RORγt+) subsets. MAIT cells have emerged in recent years as crucial players in the effective mucosal immunity and the association of a broad spectrum of disease development. However, detailed molecular mechanisms in regulating MAIT cell development and function remain unclear. Recent studies indicate the involvement of microRNAs in MAIT cell regulation, but few individual miRNAs have been identified, that play the role. To investigate the role of microRNA-155 (miR155) in the development of MAIT cells, we used both gain- and loss-of-function strategies. Using thymus-specific miR-155 knock-in mouse model, it was identified that overexpression of miR-155 significantly reduced numbers and frequencies of MAIT cells in thymus and all peripheral lymphoid and mucosal tissues. Furthermore, MAIT cells with miR-155 overexpression showed interrupted maturation with down regulated PLZF expression and reversed CD8+/CD4−CD8− MAIT subsets distribution. Strikingly, miR-155 overexpression perturbed MAIT17 cell differentiation, and transiently induced miR-155 overexpression inhibited peripheral MAIT cells IL-17 production. Using conventional miR-155 deletion mice model, we found that germline miR-155 deletion did not significantly interrupting MAIT cell development and peripheral tissue MAIT cell differentiation and function. Overall, our results indicate that adequate miR-155 expression is required for MAIT cell development, effector subsets differentiation and function.