Histone Deacetylase SIRT1 Negatively Regulates the Differentiation of Interleukin-9-Producing CD4(+) T Cells.
Distinct metabolic programs support the differentiation of CD4(+) T cells into separate functional subsets. In this study, we investigated metabolic mechanisms underlying the differentiation of IL-9-producing CD4(+) T cells (Th9) in allergic airway inflammation and cancerous tumors. We found that histone deacetylase SIRT1 negatively regulated Th9 cell differentiation. A deficiency of SIRT1 induced by either conditional deletion in mouse CD4(+) T cells or the use of small interfering RNA (siRNA) in mouse or human T cells increased IL-9 production, whereas ectopic SIRT1 expression inhibited it. Notably, SIRT1 inhibited Th9 cell differentiation that regulated anti-tumor immunity and allergic pulmonary inflammation. Glycolytic activation through the mTOR-hypoxia-inducible factor-1α (HIF1α) was required for the differentiation of Th9 cells that conferred protection against tumors and is involved in allergic airway inflammation. Our results define the essential features of SIRT1-mTOR-HIF1α signaling-coupled glycolytic pathway in inducing Th9 cell differentiation, with implications for metabolic reprogramming as an immunotherapeutic approach.
Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Yu
Y
Wang
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China.
Yujing
Y
Bi
Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Xi
X
Chen
Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Chunxiao
C
Li
Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Yan
Y
Li
Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Zhengguo
Z
Zhang
Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Jian
J
Wang
Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Yun
Y
Lu
Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
Qing
Q
Yu
Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Huilin
H
Su
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Hui
H
Yang
Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: liugw@bnu.edu.cn.
Guangwei
G
Liu
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D006019:Glycolysis; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D016906:Interleukin-9 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008545:Melanoma / Q000276:immunology*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015533:Transcriptional Activation; D000099151:MAP Kinase Kinase Kinase 7
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016906:Interleukin-9; D020930:MAP Kinase Kinase Kinases; D034741:RNA, Small Interfering; D056564:Sirtuin 1; D058570:TOR Serine-Threonine Kinases; D000099151:MAP Kinase Kinase Kinase 7; C497443:Hif1a protein, mouse; C546843:mTOR protein, mouse; C470545:Sirt1 protein, mouse
SIRT1; T cell differentiation; Th9 cells; allergic airway inflammation; glycolysis; metabolism; tumor