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 (IFN gamma) signaling network. We identified several of these IFN gamma-associated genes as direct miR-142-3p targets and observed excessive IFN gamma 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 IFN gamma responses.