title: Tsc1 expression by dendritic cells is required to preserve T-cell homeostasis and response.
abstract: Dendritic cells (DCs) are pivotal to the induction of adaptive T-cell immune responses. Recent evidence highlights a critical role of tuberous sclerosis complex 1 (Tsc1), a primarily upstream negative regulator of mammalian target of rapamycin (mTOR), in DC development, but whether and how Tsc1 directly regulate mature DC function in vivo remains elusive. Here we show that selective disruption of Tsc1 in DCs results in a lymphoproliferative disorder with the spontaneous activation of T cells. Tsc1 deficiency results in the activation of mTORC1-PPARγ pathway, which leads to the upregulation of neuropilin-1 (Nrp1) expression on DCs to stimulate naive T-cell proliferation. However, Tsc1-deficient DCs have defects in the ability to induce antigen-specific T-cell responses in vitro and in vivo owing to impaired survival during antigen transportation and presentation. Indeed, Tsc1 promotes DC survival through restraining independent mTORC1 and ROS-Bim pathways. Our study identifies Tsc1 as a crucial signaling checkpoint in DCs essential for preserving T-cell homeostasis and response.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
authors.forename: Yuechen
authors.initials: Y
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Li
authors.affiliation: Nanlou Respiratory Department, Chinese PLA General Hospital, Beijing 100853, China.|Department of Respiratory Medicine, The Second affiliated hospital of Nanchang University, Nanchang, Jiangxi 33000, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department of Medical Microbiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Medical Microbiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Xue
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
authors.forename: Zhina
authors.initials: Z
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
authors.forename: Song
authors.initials: S
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
authors.forename: Chunming
authors.initials: C
authors.lastname: Fang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Niu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
authors.forename: Zhongchao
authors.initials: Z
authors.lastname: Han
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Department of Hematology, First Affiliated Hosptial of Kunming Medical University, Kunming 650032, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Medical Microbiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liao
authors.affiliation: Nanlou Respiratory Department, Chinese PLA General Hospital, Beijing 100853, China.|Department of Respiratory Medicine, The Second affiliated hospital of Nanchang University, Nanchang, Jiangxi 33000, China.
authors.forename: Guogang
authors.initials: G
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Feng
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology
chemical_list: D046912:Multiprotein Complexes; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases