Abstract
Regulatory T (Treg) 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 Treg cell function. 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 significant decrease in the abundance and suppressive capacity of Treg cells. Expression profiling of miR-142–deficient Treg 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 Treg cells. Ifng ablation rescued the Treg cell homeostatic defect and alleviated development of autoimmunity in Foxp3CremiR-142fl/fl mice. Thus, our findings implicate miR-142 as an indispensable regulator of Treg cell homeostasis that exerts its function by attenuating IFNγ responses.
Highlights
Regulatory T (Treg) cells are vital in maintaining immune self-tolerance and restraining aberrant immune responses against infections [1,2]
The role of miR-142 in Treg cell biology thymus and secondary lymphoid organs (S1A–S1C Fig), indicating that miR-142 plays an important role in Treg cell development and homeostasis
MiR-142 is dynamically expressed during T-cell development: Its abundance gradually increases following T-cell maturation in the thymus and reaches a peak at the single positive (SP) thymocyte stage; mature T cells that egress from the thymus into periphery display a somewhat reduced miR-142 expression in comparison to SP thymocytes (S1D Fig)
Summary
Regulatory T (Treg) cells are vital in maintaining immune self-tolerance and restraining aberrant immune responses against infections [1,2]. An X chromosome–linked member of the forkhead box/winged helix family of transcription factors, is a master regulator of the genetic program that governs development and suppressive activity of Treg cells. Humans and mice that carry loss-of-function Foxp mutations develop a fatal autoimmune disease due to impaired Treg cell activity [3,4,5,6,7]. The majority of Treg cells are generated in the thymus (tTreg cells) through a selection process that favors cells with a strong functional T cell receptor. The role of miR-142 in Treg cell biology
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