title: Critical role of the tumor suppressor tuberous sclerosis complex 1 in dendritic cell activation of CD4 T cells by promoting MHC class II expression via IRF4 and CIITA.
abstract: Dendritic cell (DC) maturation is characterized by upregulation of cell-surface MHC class II (MHC-II) and costimulatory molecules, and production of a variety of cytokines that can shape both innate and adaptive immunity. Paradoxically, transcription of the MHC-II genes, as well as its activator, CIITA, is rapidly silenced during DC maturation. The mechanisms that control CIITA/MHC-II expression and silencing have not been fully understood. We report in this article that the tumor suppressor tuberous sclerosis complex 1 (TSC1) is a critical regulator of DC function for both innate and adaptive immunity. Its deficiency in DCs results in increased mammalian target of rapamycin (mTOR) complex 1 but decreased mTORC2 signaling, altered cytokine production, impaired CIITA/MHC-II expression, and defective Ag presentation to CD4 T cells after TLR4 stimulation. We demonstrate further that IFN regulatory factor 4 can directly bind to CIITA promoters, and decreased IFN regulatory factor 4 expression is partially responsible for decreased CIITA/MHC-II expression in TSC1-deficient DCs. Moreover, we identify that CIITA/MHC-II silencing during DC maturation requires mTOR complex 1 activity. Together, our data reveal unexpected roles of TSC1/mTOR that control multifaceted functions of DCs.
authors.affiliation: Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Pan
authors.forename: Thomas F
authors.initials: TF
authors.lastname: O'Brien
authors.forename: Gabriela
authors.initials: G
authors.lastname: Wright
authors.forename: Jialong
authors.initials: J
authors.lastname: Yang
authors.forename: Jinwook
authors.initials: J
authors.lastname: Shin
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Wright
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhong
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001854:Bone Marrow Cells / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D008213:Lymphocyte Activation; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000099218:Interferon Regulatory Factor-4
chemical_list: D000949:Histocompatibility Antigens Class II; D050835:Interferon Regulatory Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D051197:Toll-Like Receptor 4; D015534:Trans-Activators; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000099218:Interferon Regulatory Factor-4; C083728:MHC class II transactivator protein; C493487:Tlr4 protein, mouse; C000624651:Tsc1 protein, mouse