Excessive miR-27 expression impairs regulatory T cell-mediated immunological tolerance

Abstract

Abstract MicroRNAs (miRNAs) are tightly regulated in the immune system as aberrant expression of miRNAs often results in hematopoietic malignancies and autoimmune diseases. Previously, elevated levels of miR-27 in T cells isolated from multiple sclerosis patients has been suggested to facilitate disease progression through inhibiting Th2 immunity and promoting pathogenic Th1 responses. Here we show while mice with T cell-specific overexpression of miR-27 harbor dysregulated Th1 responses and develop autoimmune pathology, these disease phenotypes are not driven by miR-27 in effector T cells in a cell autonomous manner but rather resulted from a perturbed regulatory T (Treg) cell compartment. Excessive miR-27 expression in T cells severely impairs thymic Treg cell development and TGFb-mediated conversion of peripheral Treg cells from conventional T (Tconv) cells. Moreover, Treg cells with exaggerated miR-27-mediated gene regulation exhibit diminished homeostatic potential and suppressor function in vivo. Mechanistically, miR-27 represses a subset of genes that play critical roles in controlling multiple aspects of Treg cell biology. Collectively, our data show miR-27 functions as a key regulator in Treg cell development and function and suggest that proper regulation of miR-27 is pivotal to safeguard Treg cell-mediated immunological tolerance.