ATF4 Regulates CD4+ T Cell Immune Responses through Metabolic Reprogramming

Abstract

SUMMARYT 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.

Anxiolytic Drug FGIN-1-27 Ameliorates Autoimmunity by Metabolic Reprogramming of Pathogenic Th17 Cells

“…Our data are in accordance with a recently published report where ATF4 promotes amino acid synthesis and deficiency in ATF4 resulted in increased Th17 responses 35 . Previously, activation of the AAR by the small molecule halofuginone has been shown to down-regulate Th17 responses 20 .…”

T Cell Activation Depends on Extracellular Alanine

“…Uncharged tRNAs activate GCN2 to inhibit translation (Harding et al, 2000;Pakos-Zebrucka et al, 2016). GCN2 induces expression of ATF4 that upregulates the expression of amino acid transporters and metabolic genes (Yang et al, 2018). To test whether this stress response is activated by alanine deprivation, naive CD4 + T cells were stimulated in media containing either cFBS, dFBS, or dFBS + alanine.…”

The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities

“…PERK pathway regulator ATF4 enhances CD4 + T cells glycolysis and modulates mTORC1 activation. The ATF4-deficient CD4 + T cells are prone to differentiate into Th17 cells instead of Th1 in the EAE model (78). ER stress induces Treg plasticity as well.…”

“…ATF4 positively regulates CD4 + T cells glycolysis, glutaminolysis, and oxidative phosphorylation (78 was found to play important role in regulation of plasma cell differentiation and antibody production as well (110). Different from XBP1s, IRE1α regulates both differentiation and antibody production in B cells.…”