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

• Published in: PLoS biology Vol. 14; no. 2; p. e1002370
• Main Authors: Wang, Hong-Xia, Shin, Jinwook, Wang, Shang, Gorentla, Balachandra, Lin, Xingguang, Gao, Jimin, Qiu, Yu-Rong, Zhong, Xiao-Ping
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.02.2016; Public Library of Science (PLoS)
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Biology and Life Sciences; Cell Differentiation; Cell Lineage; Chemokines - metabolism; Mechanistic Target of Rapamycin Complex 1; Medicine and Health Sciences; Mice, Inbred C57BL; Multiprotein Complexes - metabolism; People and Places; Regulatory-Associated Protein of mTOR; Research and Analysis Methods; T-Lymphocytes - physiology; Thymus Gland - immunology; Thymus Gland - metabolism; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.1002370

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.