microRNA-142 guards against autoimmunity by controlling T(reg) cell homeostasis and function

Regulatory T (T(reg)) cells are critical in preventing aberrant immune responses. Posttranscriptional control of gene expression by microRNA (miRNA) has recently emerged as an essential genetic element for T(reg) cell function. Here, we report that mice with T(reg) cell–specific ablation of miR-142 (hereafter Foxp3(Cre)miR-142(fl/fl) mice) developed a fatal systemic autoimmune disorder due to a breakdown in peripheral T-cell tolerance. Foxp3(Cre)miR-142(fl/fl) mice displayed a significant decrease in the abundance and suppressive capacity of T(reg) cells. Expression profiling of miR-142–deficient T(reg) cells revealed an up-regulation of multiple genes in the interferon gamma (IFNγ) signaling network. We identified several of these IFNγ-associated genes as direct miR-142-3p targets and observed excessive IFNγ production and signaling in miR-142–deficient T(reg) cells. Ifng ablation rescued the T(reg) cell homeostatic defect and alleviated development of autoimmunity in Foxp3(Cre)miR-142(fl/fl) mice. Thus, our findings implicate miR-142 as an indispensable regulator of T(reg) cell homeostasis that exerts its function by attenuating IFNγ responses.