title: 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.
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, North Carolina, United States of America.|Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Jinwook
authors.initials: J
authors.lastname: Shin
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, North Carolina, United States of America.|School of Laboratory Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Shang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Balachandra
authors.initials: B
authors.lastname: Gorentla
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, North Carolina, United States of America.|School of Laboratory Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xingguang
authors.initials: X
authors.lastname: Lin
authors.affiliation: School of Laboratory Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Jimin
authors.initials: J
authors.lastname: Gao
authors.affiliation: Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Yu-Rong
authors.initials: YR
authors.lastname: Qiu
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, North Carolina, United States of America.|Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America.|Hematologic Malignancies and Cellular Therapies Program, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D018925:Chemokines / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D000076223:Regulatory-Associated Protein of mTOR; D013601:T-Lymphocytes / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; D046912:Multiprotein Complexes; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases