Hyperinsulinemia promotes atherosclerosis by inducing metabolic reprogramming of autoreactive CD4+ T cells 2359

Abstract Description Apolipoprotein B (ApoB)-specific CD4+ T cells predominantly exhibit Treg-like signatures in healthy mice and humans but some acquire proinflammatory phenotypes that contribute to atherosclerosis progression. The mechanisms driving this phenotype switching are largely unknown. We demonstrate that exposure to a western diet (WD) induces an accumulation of highly glycolytic, interferon γ-producing effector memory (TEM) and, more specifically, ApoB reactive (ApoB+) CD4+ T cells in Apoe-/- mice. Combined CITE-Seq and TCR sequencing demonstrated that blood CD4+ T cells in humans with advanced coronary artery disease were similarly enriched for glycolytic, inflammatory TEM and ApoB+ CD4+ T cells. CD4+ T cell-specific depletion of the glucose transporter Glut1 (CD4Cre-ERT2 Glut1fl/fl) prevented this pro-inflammatory CD4+ T cell phenotype and reduced atherosclerosis in Apoe-/- mice. Glut1 deficiency in Foxp3 lineage tracker (Foxp3eGFP-Cre-ERT2 Glut1fl/flROSA26fl-stop-fl-RFP) Apoe-/- mice mitigated the conversion of Tregs to proatherogenic Foxp3- exTreg cells. By utilizing Apoe-/- mice with CD4+ T cell-specific insulin receptor (InsR) deficiency (CD4Cre-ERT2 InsRfl/fl), we mechanistically identified hyperinsulinemia as a critical driver of the diet-related metabolic reprogramming and proinflammatory conversion of CD4+ T cells during atherogenesis. Our findings may pave the way for targeted metabolic interventions to prevent or treat the proatherogenic conversion of CD4+ T cells. Funding Sources This work was supported by the German Research Foundation (NE 2574/1-1 to FSN), and the National Institutes of Health (R35 HL145241 to KL, AI139749 and AI101423 to CAB). Topic Categories Translational and Interventional Immunology (TI)