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

doi:10.1016/j.celrep.2018.04.032

ATF4 Regulates CD4⁺ T Cell Immune Responses through Metabolic Reprogramming

Cell Rep. 2018 May 8;23(6):1754-1766. doi: 10.1016/j.celrep.2018.04.032.

Authors

Xi Yang¹, Rui Xia², Cuihua Yue³, Wensi Zhai³, Wenwen Du⁴, Qianting Yang⁵, Huiling Cao⁶, Xiaojuan Chen⁷, Danielle Obando⁸, Yibei Zhu⁹, Xinchun Chen¹⁰, Jane-Jane Chen¹¹, Jon Piganelli¹², Peter Wipf¹³, Yu Jiang¹⁴, Guozhi Xiao⁶, Changping Wu¹⁵, Jingting Jiang¹⁵, Binfeng Lu¹⁶

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen 518055, China.
⁷ 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.
⁸ Department of Immunology, School of Medicine, University of Pittsburgh, EBST E1047, 200 Lothrop Street, Pittsburgh, PA 15261, USA.
⁹ 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.
¹⁰ 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.
¹¹ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹² Division of Immunogenetics, Department of Pediatrics, Rangos Research Center, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
¹³ Department of Chemistry and Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA.
¹⁴ Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
¹⁵ Department of Oncology, the Third Affiliated Hospital, Soochow University, Changzhou 213003, Jiangsu, China.
¹⁶ 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. Electronic address: [email protected].

Abstract

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.

Keywords: ATF4; EAE; T cell; TCA cycle; Th1; Th17; amino acid; autoimmune; glycolysis; metabolism.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 4 / deficiency
Activating Transcription Factor 4 / metabolism*
Amino Acids / biosynthesis
Amino Acids / deficiency
Animals
CD4-Positive T-Lymphocytes / cytology
CD4-Positive T-Lymphocytes / immunology*
CD4-Positive T-Lymphocytes / metabolism*
Cell Proliferation
Cell Respiration
Gene Expression Regulation
Glutathione / metabolism
Glycolysis
Lymphocyte Activation / immunology
Mechanistic Target of Rapamycin Complex 1 / metabolism
Mice, Inbred C57BL
Mice, Knockout
Oxidation-Reduction
Oxygen Consumption
Sulfhydryl Compounds / metabolism
Th1 Cells / immunology

Substances

Amino Acids
Sulfhydryl Compounds
Activating Transcription Factor 4
Mechanistic Target of Rapamycin Complex 1
Glutathione

Abstract

Publication types

MeSH terms

Substances

Grants and funding