Abstract
Regulatory T cells (Tregs) are considered important for controlling the onset and development of autoimmune disease. Although studies have shown that miR-21 is expressed at higher levels in Treg cells, it remains largely elusive whether miR-21 regulates the immune-suppressive function of Tregs. In the current study, we generated mice lacking miR-21 specifically in their Tregs and investigated the role of miR-21 in regulating Treg function both in vitro and in vivo. Our study revealed that Tregs lacking miR-21 exhibit normal phenotype and unaltered function in suppressing T cell proliferation and dendritic cell activation in vitro. However, compared with miR-21-sufficient Tregs, they produce significant more IL-17 and IL-10 when under pathogenic Th17-priming condition. Adenoviral delivery of miR-21 into Treg cells is able to reduce the expression of both IL-17 and IL-10. Mechanistic study revealed that miR-21 down-regulates IL-10 expression through direct targeting of IL-10, and suppresses reprogramming of Tregs into IL-17-secreting cells through down-regulating Stat3 activity. However, we detected no significant or marginal difference in the development of various autoimmune diseases between wild type mice and mice with Treg-specific deletion of miR-21. In conclusion, our study demonstrated that miR-21 in Tregs regulates diametrically opposed biological Treg functions and is largely dispensable for the development of autoimmune disease.
Highlights
Regulatory T (Treg) cells are a specialized subpopulation of T cells that play crucial roles in maintaining immune homeostasis and preventing autoimmunity [1,2,3]
Since Treg cells that are defective in inhibiting effector T cells in vivo may display normal in vitro suppressive activity, we examined whether miR-21 affects Treg function in vivo using three mouse models of autoimmune disease, all of which are closely related to Th17-mediated inflammatory immune pathogenesis
While studies have shown that miR-21 promotes Th17 differentiation and glucose metabolism of pathogenic Th17 cells, our current study suggests that miR-21 in Treg cells suppresses the expression of IL-17 and IL-10 under inflammatory condition but is largely dispensable for the development of autoimmune disease
Summary
Regulatory T (Treg) cells are a specialized subpopulation of T cells that play crucial roles in maintaining immune homeostasis and preventing autoimmunity [1,2,3]. Dysregulation in Treg cell frequency or function may lead to the development of autoimmune disease. The Foxp protein has generally been described as a master regulator of Treg cell development and function. Scurfy mice and patients carrying Foxp gene mutation display lymphoproliferation, lymphocytic infiltration, and multiorgan autoimmune diseases [4, 5]. Autoimmune diseases in the scurfy mice can be prevented by adoptive transfer of Treg cells [6].
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