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.
Highlights
The thymus is the primary organ for T cell development and generation of a diverse repertoire of T cells that are crucial for host defense but are self-tolerated
Thymopoiesis and thymus function rely on orchestrated interaction between multiple cell types representing different origins
Using a mouse model with mTOR complex 1 (mTORC1) selectively ablated in thymic epithelial cell (TEC), we demonstrate that mTORC1 in TECs plays critical roles in thymopoiesis and thymus function
Summary
The thymus is the primary organ for T cell development and generation of a diverse repertoire of T cells that are crucial for host defense but are self-tolerated. TECs include cortical and medullary subsets that reside in different localizations in the thymus and perform distinct functions. While cortical thymic epithelial cells (cTECs) are important for positive selection of conventional TCRα/β T (cαβT) cells, medullary thymic epithelial cells (mTECs) induce negative selection of highly self-reactive T cells and generation of regulatory T cells (Tregs) [2,3,4,5]. Several transcription factors such as Foxn and Aire and receptors such as RANK, CD40, and LTβR are found important for TEC development/function [7,8,9], mechanisms that control thymopoiesis and mTEC/cTEC ratios are poorly understood
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