Thymic epithelial miR-155 promotes regulatory T cell development through safeguarding medullary thymic epithelial cell maturation

Abstract

During thymocyte development, medullary thymic epithelial cells (mTECs) provide appropriate instructive cues in the thymic microenvironment for not only negative selection but also the generation of regulatory T (Treg) cells. Here, we identify that miR-155, a microRNA whose expression in Treg cells has previously been shown to be crucial for their development and homeostasis, also contributes to thymic Treg (tTreg) cell differentiation by promoting mTEC maturation. Mechanistically, we show that RANKL stimulation induces expression of miR-155 to safeguard the thymic medulla through targeting multiple known and previously uncharacterized molecules within the TGFβ signaling pathway, which is recognized for its role in restricting the maturation and expansion of mTECs. Our work uncovers a miR-155-TGFβ axis in the thymic medulla to determine mTEC maturity and, consequently, the quantity of tTreg cells and suggests that miR-155 ensures proper tTreg cell development in both cell-intrinsic and -extrinsic manners.