Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior

  • Cell. 2019 Oct 31;179(4):864-879.e19. doi: 10.1016/j.cell.2019.10.001.
Ke-Qi Fan  1 ,  Yi-Yuan Li  1 ,  Hao-Li Wang  1 ,  Xin-Tao Mao  1 ,  Jin-Xin Guo  1 ,  Fei Wang  1 ,  Ling-Jie Huang  2 ,  Yi-Ning Li  1 ,  Xiang-Yu Ma  3 ,  Zheng-Jun Gao  1 ,  Wei Chen  4 ,  Dan-Dan Qian  5 ,  Wen-Jin Xue  5 ,  Qian Cao  2 ,  Lei Zhang  2 ,  Li Shen  1 ,  Long Zhang  1 ,  Chao Tong  1 ,  Jiang-Yan Zhong  1 ,  Wei Lu  5 ,  Ling Lu  6 ,  Ke-Ming Ren  2 ,  Guisheng Zhong  7 ,  Yuan Wang  4 ,  Mingliang Tang  5 ,  Xin-Hua Feng  1 ,  Ren-Jie Chai  8 ,  Jin Jin  9
Affiliations
  • 1. MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
  • 2. Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China.
  • 3. Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing 210096, China; Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China; Institute for Stem Cell and Regeneration, Chinese Academy of Science, Beijing, China.
  • 4. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
  • 5. Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing 210096, China.
  • 6. Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, 210008, Jiangsu, China.
  • 7. iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • 8. Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing 210096, China; Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China; Institute for Stem Cell and Regeneration, Chinese Academy of Science, Beijing, China. Electronic address: [email protected].
  • 9. MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China. Electronic address: [email protected].
PMID: 31675497 DOI: 10.1016/j.cell.2019.10.001
Abstract

Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the pathological role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4+ T cells protects mice from stress-induced anxiety-like behavior. Physical stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4+ T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4+ T cell-derived xanthine acts on oligodendrocytes in the left amygdala via Adenosine Receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4+ T cells. Our study implicates a critical link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior.

Keywords
AdorA1; IRF-1; T cell; amygdala; anxiety; leukotriene B4; purine metabolism; stress; xanthine.
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