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

Fan, KQ;Li, YY;Wang, HL;Mao, XT;Guo, JX;Wang, F;Huang, LJ;Li, YN;Ma, XY;Gao, ZJ;Chen, W;Qian, DD;Xue, WJ;Cao, Q;Zhang, L;Shen, L;Zhang, L;Tong, C;Zhong, JY;Lu, W;Lu, L;Ren, KM;Zhong, G;Wang, Y;Tang, M;Feng, XH;Chai, RJ;Jin, J;

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. Copyright 2019 Elsevier Inc. All rights reserved.