miR-155 promotes T reg cell development by 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 (T reg) cells. Here, we identify that miR-155, a microRNA whose expression in T reg cells has previously been shown to be crucial for their development and homeostasis, also contributes to thymic T reg (tT reg) 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 tT reg cells and suggests that miR-155 ensures proper tT reg cell development in both cell-intrinsic and -extrinsic manners.

Cell‐intrinsic and ‐extrinsic roles of miRNAs in regulating T cell immunity

“…Consequently, the quantity of Treg cells particularly in the thymus was also impacted. 82 Mechanistically, we have further demonstrated that miR-155 ensures proper mTEC maturation through targeting a network of molecules (including TGFβR2, SMAD2/3, and RNF111) within the TGFβ signaling pathway. As the TGFβ signaling pathway had been previously shown to play a key role in limiting the maturation and expansion of mTECs, 83 our work reveals a previously unappreciated role of miR-155 in safeguarding mTEC maturation through counteracting the negative effects from the continuous presence of intrathymic TGFβ, thereby establishing an optimal thymic microenvironment favorable for thymic Treg development (Figure 2a).…”

“…As the TGFβ signaling pathway had been previously shown to play a key role in limiting the maturation and expansion of mTECs, 83 our work reveals a previously unappreciated role of miR-155 in safeguarding mTEC maturation through counteracting the negative effects from the continuous presence of intrathymic TGFβ, thereby establishing an optimal thymic microenvironment favorable for thymic Treg development (Figure 2a). 82 This study is the first demonstration of an individual miRNA with functional importance in driving Treg cell differentiation in both T cell-intrinsic and -extrinsic manners. It also suggests that additional attention should be paid to stromal cells residing in the same microenvironments to better understand the biological impact of a given miRNA on a selective T cell response or other immunological processes.…”

“…81 As discussed above, in addition to its role in mediating negative selection, the thymic medulla represents a specific site for establishing self-tolerance via the generation of Treg cells. To this end, we have recently demonstrated that miR-155, a miRNA whose expression in T cells is critical for Treg cell development and homeostasis, 48,82 also plays a pivotal role in driving thymic Treg cell differentiation through promoting mTEC maturation. 82 To this end, miR-155 is preferentially expressed in mature CD80 hi MHCII hi mTECs in part via a RANK signaling-dependent manner.…”

“…To this end, we have recently demonstrated that miR-155, a miRNA whose expression in T cells is critical for Treg cell development and homeostasis, 48,82 also plays a pivotal role in driving thymic Treg cell differentiation through promoting mTEC maturation. 82 To this end, miR-155 is preferentially expressed in mature CD80 hi MHCII hi mTECs in part via a RANK signaling-dependent manner. Elevated expression of miR-155 in mTECs is important for maintaining optimal mTEC maturation as TEC-specific deletion of miR-155 leads to a diminished mature mTEC population despite the overall thymic cellularity remaining unaltered.…”

Epigenetic modifications in thymic epithelial cells: an evolutionary perspective for thymus atrophy

“…The role of miR-155 was reviewed in detail and involved in the Treg cells development [ 74 ]. Moreover, miR-155 can augment the maturation of mTECs via modulating the TGF-β signaling pathway [ 75 ]. Remarkably, a negative feedback regulation loop was unveiled between miR-146a and NF-κB signaling pathway via combining to TNF receptor-associated factor 6 (TRAF6) [ 76 ].…”