A Non-redundant Role for Thymic Epithelial MicroRNA-155 in the Generation of Tregs

miR-155 is a non-coding RNA that is highly upregulated in regulatory T-cells (Tregs), the adaptive immune cells specialized in suppressing autoreactive T cells in order to maintain tolerance and homeostasis. While several studies have confirmed the importance of miR-155 in modulating IL-2R sensitivity to maintain Treg homeostasis, alternative pathways through which miR-155 regulates Treg development remain to be elucidated. In addition to its role in T cells, through taking cell-type specific gene targeting approaches, we demonstrate that miR-155 in Thymic Epithelial Cells (TECs) is equally important in promoting thymic Treg (tTreg) development. In particular, we show that CD80hiMHC IIhi medullary TECs (mTECs), a mature mTEC subset crucial for the generation of tTregs, express high levels of miR-155 and that deletion of TEC-specific miR-155 led to a selective reduction in this mTEC population. Further investigation into the role of thymic epithelial miR-155 pointed to a potential mechanism whereby miR-155 targeting of SMAD3 attenuates TGF-β signaling in mTECs. As the role of TGF-β signaling in controlling the generation of mTECs has been previously established, here we propose a miR-155-SMAD3 axis that regulates TGF-β signaling in the thymic medulla to determine mTEC maturity and, in consequence, the quantity of developing tTregs