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

摘要

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. The thymus is essential for making T cells but undergoes age- or stress-associated atrophy. This study demonstrates that mTOR complex 1 in thymic epithelial cells is crucial for correct thymic architecture and the production of mature T cells. Author Summary The thymus is the primary organ for T cell generation. Abnormal thymus function profoundly affects host immunity and numerous diseases. Thymopoiesis and thymus function rely on orchestrated interaction between multiple cell types representing different origins. Among them, thymic epithelial cells (TECs) are crucial for thymus development and maintenance and T cell generation. How TEC development and function are regulated is poorly understood. The mammalian/mechanistic target of rapamycin (mTOR), a serine/threonine kinase, signals with two complexes, mTORC1 and mTOC2, to control metabolism, growth, proliferation, and survival. Using a mouse model with mTORC1 selectively ablated in TECs, we demonstrate that mTORC1 in TECs plays critical roles in thymopoiesis and thymus function. Absence of mTORC1 results in impaired TEC maturation and function, altered thymic architecture, severe thymic atrophy, and impaired development of virtually all T-cell lineages. Moreover, it also causes increased generation of IL-17–producing γδT (γδT17) cells and fetal-specific γδT subsets in adult thymus, revealing that mTORC1 in TECs is central for temporal control of γδT17 differentiation and TCRVγ/δ recombination. Our results establish mTORC1 as a central regulator for TEC development/function and for the establishment of normal thymic environment for proper T cell development. We suggest modulating mTORC1 activity as a strategy for preventing thymic involution/atrophy.