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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / metabolism
  • Amygdala / pathology
  • Animals
  • Anxiety / genetics
  • Anxiety / immunology
  • Anxiety / metabolism*
  • Anxiety / physiopathology
  • Behavior, Animal / physiology*
  • Brain Diseases, Metabolic / genetics
  • Brain Diseases, Metabolic / metabolism*
  • Brain Diseases, Metabolic / physiopathology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / pathology
  • Disease Models, Animal
  • Humans
  • Mice
  • Mitochondrial Dynamics / genetics
  • Oligodendroglia / metabolism
  • Oligodendroglia / pathology
  • Single-Cell Analysis
  • Stress, Psychological / genetics
  • Stress, Psychological / metabolism*
  • Stress, Psychological / physiopathology
  • Transcriptome / genetics
  • Xanthine / metabolism


  • Xanthine