ATF4 Regulates CD4+ T Cell Immune Responses through Metabolic Reprogramming
Xi Yang,
Rui Xia,
Cuihua Yue,
Wensi Zhai,
Wenwen Du,
Qianting Yang,
Huiling Cao,
Xiaojuan Chen,
Danielle Obando,
Yibei Zhu,
Xinchun Chen,
Jane-Jane Chen,
Jon Piganelli,
Peter Wipf,
Yu Jiang,
Guozhi Xiao,
Changping Wu,
Jingting Jiang,
Binfeng Lu
Affiliations
Xi Yang
Department of Immunology, School of Medicine, University of Pittsburgh, EBST E1047, 200 Lothrop Street, Pittsburgh, PA 15261, USA; School of Medicine, Tsinghua University, HaiDian, Beijing 100084, China
Rui Xia
Department of Immunology, School of Medicine, University of Pittsburgh, EBST E1047, 200 Lothrop Street, Pittsburgh, PA 15261, USA; Department of Immunology, Institute of Medical Biotechnology, Soochow University, Suzhou 215007, China; The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
Cuihua Yue
Department of Immunology, School of Medicine, University of Pittsburgh, EBST E1047, 200 Lothrop Street, Pittsburgh, PA 15261, USA; Department of Oncology, the Third Affiliated Hospital, Soochow University, Changzhou 213003, Jiangsu, China
Wensi Zhai
Department of Immunology, School of Medicine, University of Pittsburgh, EBST E1047, 200 Lothrop Street, Pittsburgh, PA 15261, USA; Department of Oncology, the Third Affiliated Hospital, Soochow University, Changzhou 213003, Jiangsu, China
Wenwen Du
Department of Immunology, School of Medicine, University of Pittsburgh, EBST E1047, 200 Lothrop Street, Pittsburgh, PA 15261, USA; Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
Qianting Yang
Department of Immunology, School of Medicine, University of Pittsburgh, EBST E1047, 200 Lothrop Street, Pittsburgh, PA 15261, USA; Guangdong Key Laboratory for Emerging Infectious Disease, Shenzhen Key Laboratory of Infection and Immunity, Third People’s Hospital, Guangdong Medical College, Shenzhen, Guangdong 518112, China
Huiling Cao
Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen 518055, China
Xiaojuan Chen
Department of Immunology, School of Medicine, University of Pittsburgh, EBST E1047, 200 Lothrop Street, Pittsburgh, PA 15261, USA; Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
Danielle Obando
Department of Immunology, School of Medicine, University of Pittsburgh, EBST E1047, 200 Lothrop Street, Pittsburgh, PA 15261, USA
Yibei Zhu
Department of Immunology, School of Medicine, University of Pittsburgh, EBST E1047, 200 Lothrop Street, Pittsburgh, PA 15261, USA; Department of Immunology, Institute of Medical Biotechnology, Soochow University, Suzhou 215007, China
Xinchun Chen
Guangdong Key Laboratory for Emerging Infectious Disease, Shenzhen Key Laboratory of Infection and Immunity, Third People’s Hospital, Guangdong Medical College, Shenzhen, Guangdong 518112, China
Jane-Jane Chen
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA
Jon Piganelli
Division of Immunogenetics, Department of Pediatrics, Rangos Research Center, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
Peter Wipf
Department of Chemistry and Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA
Yu Jiang
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Guozhi Xiao
Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen 518055, China
Changping Wu
Department of Oncology, the Third Affiliated Hospital, Soochow University, Changzhou 213003, Jiangsu, China
Jingting Jiang
Department of Oncology, the Third Affiliated Hospital, Soochow University, Changzhou 213003, Jiangsu, China
Binfeng Lu
Department of Immunology, School of Medicine, University of Pittsburgh, EBST E1047, 200 Lothrop Street, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Corresponding author
Summary: T cells are strongly regulated by oxidizing environments and amino acid restriction. How T cells reprogram metabolism to adapt to these extracellular stress situations is not well understood. Here, we show that oxidizing environments and amino acid starvation induce ATF4 in CD4+ T cells. We also demonstrate that Atf4-deficient CD4+ T cells have defects in redox homeostasis, proliferation, differentiation, and cytokine production. We further reveal that ATF4 regulates a coordinated gene network that drives amino acid intake, mTORC1 activation, protein translation, and an anabolic program for de novo synthesis of amino acids and glutathione. ATF4 also promotes catabolic glycolysis and glutaminolysis and oxidative phosphorylation and thereby provides precursors and energy for anabolic pathways. ATF4-deficient mice mount reduced Th1 but elevated Th17 immune responses and develop more severe experimental allergic encephalomyelitis (EAE). Our study demonstrates that ATF4 is critical for CD4+ T cell-mediated immune responses through driving metabolic adaptation. : Oxidizing environments and availability of extracellular amino acids are major mechanisms that regulate T cell proliferation and function. Yang et al. demonstrate that ATF4 drives metabolic reprogramming, which allows CD4+ T cells to adapt to these stresses. Keywords: T cell, metabolism, EAE, Th17, Th1, ATF4, amino acid, glycolysis, TCA cycle, autoimmune
