Abstract
Abstract Regulatory T (Treg) cells are critical in preventing aberrant immune responses. Post-transcriptional gene control by microRNA (miRNA), a large class of small regulatory RNA, has recently emerged as a key genetic element required for Treg cell function. Nevertheless, specific miRNA gene(s) that play a vital role in the regulation of Treg cell activity are still unknown. Here we report that mice with Treg cell-specific ablation of miR-142 (hereafter Foxp3CremiR-142fl/fl mice) developed a fatal systemic autoimmune disorder due to a breakdown in peripheral T cell tolerance. Foxp3CremiR-142fl/fl mice displayed a sharp decrease in abundance and suppressive capacity of Treg cells. Analysis of miR-142-deficient Treg cells revealed excessive IFNγ production and dysregulated IFNγ signaling. We have identified several of the derepressed IFNγ-related genes, including Ifngr2 receptor and Hif1a transcription factor, as direct miR-142 targets. Furthermore, lowering the Hif1a gene dose in Treg cells significantly diminished the hyperactivation of peripheral effector T cells in Foxp3CremiR-142fl/flmice. Thus, miR-142 is an indispensable regulator of Treg cell development and function that mediates its control by attenuating IFNg response.
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