mTORC1 in Thymic Epithelial Cells Is Critical for Thymopoiesis, T-Cell Generation, and Temporal Control of γδT17 Development and TCRγ/δ Recombination

Abstract

Thymus is crucial for generation of a diverse repertoire of T cells essential for adaptive immunity. Although thymic epithelial cells (TECs) are crucial for thymopoiesis and T cell generation, how TEC development and function are controlled is poorly understood. We report here that mTOR complex 1 (mTORC1) in TECs plays critical roles in thymopoiesis and thymus function. Acute deletion of mTORC1 in adult mice caused severe thymic involution. TEC-specific deficiency of mTORC1 (mTORC1KO) impaired TEC maturation and function such as decreased expression of thymotropic chemokines, decreased medullary TEC to cortical TEC ratios, and altered thymic architecture, leading to severe thymic atrophy, reduced recruitment of early thymic progenitors, and impaired development of virtually all T-cell lineages. Strikingly, temporal control of IL-17-producing γδT (γδT17) cell differentiation and TCRVγ/δ recombination in fetal thymus is lost in mTORC1KO thymus, leading to elevated γδT17 differentiation and rearranging of fetal specific TCRVγ/δ in adulthood. Thus, mTORC1 is central for TEC development/function and establishment of thymic environment for proper T cell development, and modulating mTORC1 activity can be a strategy for preventing thymic involution/atrophy.

mTORC2 in Thymic Epithelial Cells Controls Thymopoiesis and T Cell Development

“…Abnormal development/function of TECs in the absence of Rictor/mTORC2 leads to moderately impaired development of cαβT cells, Tregs, and γδT cells, but more severe impairment of iNKT cells. Data from this study and our recent demonstration of a critical role for mTORC1 in TECs for thymopoiesis and T cell generation (22) establish mTOR as a central regulator in TECs to extrinsically control T cell development.…”

“…IL-17-producing γδT (γδT17) cells are predominantly generated in fetal and newborn thymus (33, 34). Two recent studies have revealed that thymic epithelial cells may foster a thymic environment for temporal control of γδT17 differentiation (22, 35) and that such temporal control of γδT17 differentiation requires mTORC1 in TECs (22). γδT17 cells mainly reside in the CD44 + CD27 − population, while IFNγ-producing γδT (γδT1) cells are enriched in the CD27 + population (34).…”

“…mTOR and its tight regulation by TSC1 in developing thymocytes intrinsically control iNKT cell development and function (15, 16, 21, 37–39). We have recently revealed that mTORC1 in TECs promotes iNKT cell development (22). Using PBS57-loaded CD1d-Tetramer (CD1dTET) and TCRβ staining, we observed decreased thymic CD1dTET + TCRβ + i NKT-cells in 3-week- and 3 month-old RictorKO mice (Figure 8A, 8B), accompanying more severe decreases of i NKT-cell total numbers (Figure 8C).…”

“…Thymic single-cell suspension as previously described with modifications (22, 25, 26). In brief, thymi were cut into small pieces (about 2mm), which were directly digested in FBS-free RPMI-1640 containing 10mg/ml collagenase type IV (Worthington) and 50mg/ml DNase I (Worthington) at 37 °C with constant orbital shaking at 100–150 rpm for 10 minutes.…”

“…Recently, we have found that the mTORC1 signal in TECs plays crucial roles in thymopoiesis and thymic function. Ablation of Raptor in TECs causes impaired TEC maturation, decreased mTEC to cTEC ratios, and altered thymic architecture, leading to severe thymic atrophy, reduced recruitment of early thymic progenitors and impaired development of virtually all T cell lineages (22). We report here that mTORC2/Rictor in TECs signals for proper thymopoiesis and T cell generation.…”