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MiR-125a targets effector programs to stabilize Treg-mediated immune homeostasis.

Pan, W;Zhu, S;Dai, D;Liu, Z;Li, D;Li, B;Gagliani, N;Zheng, Y;Tang, Y;Weirauch, MT;Chen, X;Zhu, W;Wang, Y;Chen, B;Qian, Y;Chen, Y;Fang, J;Herbst, R;Richman, L;Jallal, B;Harley, JB;Flavell, RA;Yao, Y;Shen, N;

Although different autoimmune diseases show discrete clinical features, there are common molecular pathways intimately involved. Here we show that miR-125a is downregulated in peripheral CD4(+) T cells of human autoimmune diseases including systemic lupus erythematosus and Crohn's disease, and relevant autoimmune mouse models. miR-125a stabilizes both the commitment and immunoregulatory capacity of Treg cells. In miR-125a-deficient mice, the balance appears to shift from immune suppression to inflammation, and results in more severe pathogenesis of colitis and experimental autoimmune encephalomyelitis (EAE). The genome-wide target analysis reveals that miR-125a suppresses several effector T-cell factors including Stat3, Ifng and Il13. Using a chemically synthesized miR-125a analogue, we show potential to re-programme the immune homeostasis in EAE models. These findings point to miR-125a as a critical factor that controls autoimmune diseases by stabilizing Treg-mediated immune homeostasis.