The Role And Machinism Of MiR-142-3p In Regulating Function And Apoptosis Of Induced Regulatory T Cells

Induced Regulatory t cell(iTreg),induced by CD4~+CD45RA~+na?ve t cells,has immunosuppressive function and plays an important role in maintaining immune homeostasis.Smilar to natural regulatory T cells(nTreg),iTreg clinical trials are gradually being applied to treat autoimmune diseases and prevent GVHD.Both of autophagy and apoptosis play important roles in the differentiation,survival and function of lymphocytes.Autophagy is the mechanism of cell self-degradative process to maintain survival.Tregs with abnormal autophagy function in mice can cause defective proliferation and functional.The deficiency of autophagy-related protein(ATG16L1)causes differentiation and proliferation disorders in T cells,aggravating the progression of autoimmune diseases such as SLE.In addition,histone modification is an indispensable mechanism regulating gene expression and gene silence.Deletion of the histone demethylase,KDM6A,results in a lymphocyte maturation disorder with a decrease in T lymphocytes in human peripheral blood.Downregulation of KDM6A decreases demethylation of H3K27me3,causing gene repression of the anti-apoptotic gene Bcl-2.miR-142-3p is highly expressed in Treg cells and potentially targets the ATG16L1 and KDM6A genes.Whether miR-142-3p can regulate anti-apoptotic ability and function of iTreg through controlling autophagy or histone modification.We demonstrate that miR-142-3p regulates the expression of ATG16L1 and KDM6A in iTreg by targeting directly.By knockdown of miR-142-3p,the expression of ATG16L1 can be enhanced in iTreg resulting in enhanced autophagy.On the other hand,it can also promote the demethylation of H3K27me3 and increases the Bcl-2 expression in iTreg,thereby enhancing the anti-apoptotic ability,survival and function of iTreg both in vitro and in vivo.Our results provide a new strategy that knockdown of miR-142-3p can enhance iTreg function and anti-apoptotic ability through the two pathways of ATG16L1-Foxp3 and KDM6A-H3K27me3-Bcl-2,respectively,promoting the value of iTreg clinical application.