Dendritic cell SIRT1-HIF1α axis programs the differentiation of CD4+ T cells through IL-12 and TGF-β1.
The differentiation of naive CD4(+) T cells into distinct lineages plays critical roles in mediating adaptive immunity or maintaining immune tolerance. In addition to being a first line of defense, the innate immune system also actively instructs adaptive immunity through antigen presentation and immunoregulatory cytokine production. Here we found that sirtuin 1 (SIRT1), a type III histone deacetylase, plays an essential role in mediating proinflammatory signaling in dendritic cells (DCs), consequentially modulating the balance of proinflammatory T helper type 1 (TH1) cells and antiinflammatory Foxp3(+) regulatory T cells (T(reg) cells). Genetic deletion of SIRT1 in DCs restrained the generation of T(reg) cells while driving TH1 development, resulting in an enhanced T-cell-mediated inflammation against microbial responses. Beyond this finding, SIRT1 signaled through a hypoxia-inducible factor-1 alpha (HIF1α)-dependent pathway, orchestrating the reciprocal TH1 and T(reg) lineage commitment through DC-derived IL-12 and TGF-β1. Our studies implicates a DC-based SIRT1-HIF1α metabolic checkpoint in controlling T-cell lineage specification.
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Biotherapy Research Center and Institute of Immunobiology, Fudan University, Shanghai 200032, China; liugw@fudan.edu.cn ruoning.wang@nationwidechildren.org.
Guangwei
G
Liu
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;
Yujing
Y
Bi
Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, Beijing 100191, China; and.
Lixiang
L
Xue
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Biotherapy Research Center and Institute of Immunobiology, Fudan University, Shanghai 200032, China;
Yan
Y
Zhang
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Biotherapy Research Center and Institute of Immunobiology, Fudan University, Shanghai 200032, China;
Hui
H
Yang
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Biotherapy Research Center and Institute of Immunobiology, Fudan University, Shanghai 200032, China;
Xi
X
Chen
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Biotherapy Research Center and Institute of Immunobiology, Fudan University, Shanghai 200032, China;
Yun
Y
Lu
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Biotherapy Research Center and Institute of Immunobiology, Fudan University, Shanghai 200032, China;
Zhengguo
Z
Zhang
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Biotherapy Research Center and Institute of Immunobiology, Fudan University, Shanghai 200032, China;
Huanrong
H
Liu
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Biotherapy Research Center and Institute of Immunobiology, Fudan University, Shanghai 200032, China;
Xiao
X
Wang
Center for Childhood Cancer and Blood Diseases, Hematology/Oncology and Bone Marrow Transplantation, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH 43205 liugw@fudan.edu.cn ruoning.wang@nationwidechildren.org.
Ruoning
R
Wang
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Biotherapy Research Center and Institute of Immunobiology, Fudan University, Shanghai 200032, China;
Yiwei
Y
Chu
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;
Ruifu
R
Yang
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000276:immunology*; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D056564:Sirtuin 1 / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology*
C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D018664:Interleukin-12; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
HIF1α; SIRT1; T-cell differentiation; dendritic cells; innate immunity