UC San Diego

MicroRNAs (miRNAs), a class of small non-coding RNA molecules, are key nodes in regulatory networks that fine-tune gene expression and orchestrate diverse signaling pathways that shape immune responses. Since the first study of Dicer-dependent miRNA pathway in regulatory T (Treg) cells in more than a decade ago, miRNAs have been shown to serve as key regulatory elements in controlling the development and function of this specialized CD4+ T cell subset that is indispensable for maintaining immune tolerance and homeostasis. Nevertheless, despite the rapidly accumulating knowledge of the role of miRNAs in Treg cells, our understanding of the intricate regulations of miRNAs and their targets in regulating different aspects of Treg cell biology remains limited. In this work, we demonstrate a critical role for miR-155, which ensures proper Treg cell development in the thymus. Specifically, in addition to the previously reported function of miR-155 in conferring Treg cell competitive fitness, we uncover a novel miR-155-TGFβ axis in the thymic medulla that determines medullary thymic epithelial cell (mTEC) maturity and, consequently, the quantity of thymic Treg cells. In addition to miR-155, we also identify another miRNA family, miR-15/16 that plays an important role in restricting Treg cell function and homeostasis. To this end, we find that the miR-15/16 family, miR-15b/16-2 in particular, is specifically up-regulated in Treg cells in the thymus. Nevertheless, this miRNA family does not seem to play a significant role in regulating thymic Treg cell development. Rather, it is important to control effector Treg (eTreg) cell differentiation and function in the periphery. Mechanistically, the miR-15/16 family targets a network of genes, including a transcription factor, IRF4 that are critical for the establishment of the eTreg cell program. Collectively, our findings highlight both cell-extrinsic and –intrinsic roles of miRNAs mediated by miR-155 and miR-15/16, respectively in controlling Treg cell biology. Our work not only reveals novel mechanisms by which miRNAs regulate Treg cell-mediated immune tolerance but also provides molecular insights that will undoubtedly aid in developing innovative strategies targeting Treg cells to treat a wide range of immunological disorders.