MicroRNA-31 Negatively Regulates Peripherally Derived Regulatory T Cell Generation By Repressing Gprc5a

Dysfunctional Fox P3+ regulatory T(Treg) cells are identified in several autoimmune diseases including mutiple sclerosis(MS). One of failures of Treg cell-mediated immunoregulation is inadequate numbers of Treg cells that may be due to defective induction of adaptive or inducible Treg(pTreg) cells in the periphery. pTreg cell differention requires TCR signaling and the cytokines TGF-?1 and IL-2. However, key intrinsic factors controlling the pTreg cell induction remain unclear. Retinoic acid(RA) regulates the expression of genes required for cell proliferation, differentiation and survival by binding its nuclear retinoic acid receptors(RARs) and retinoid X receptors(RXRs). Although RA has been shown to enforce pTreg cell differentiation, the mechanism by which RA promotes pTreg cell induction is ill defined. Here we found that the microRNA miR-31 was preferentially diminished in TGF-?1-induced iTreg cells, was directly inhibited by FoxP3, and negatively regulated na?ve CD4+ T cell differention into i Treg cells. The conditional deletion of miR-31 in CD4+ T cells resulted in enhanced induction of pTreg cells in the periphery, and decreased serverity of experimental autoimmune encephalomyelitis(EAE), an animal model of MS. Unexpectedly, we identified Gprc5 a as a direct target of miR-31. Gprc5 a is also known as retinoic acid-inducible protein 3 harbouring the functional RAR/RXR binding sites of RA in its core promoter.Gprc5 a was targeted by miR-31 through direct binding to its 3’ untranslated regions(3’ UTR), and its difficiency led to impairment of pTreg cell induction and increased EAE severity. Given RA is functionally important for the peripheral differentiation of pTreg cells, our data identify miR-31 and its novel target Gprc5 a as critical regulators for pTreg cell differentiation, suggesting a previously unrecognized epigenetic mechanism for impaired pTreg cell induction in autoimmune disease.