Defective autophagy drives the transition from regulatory Tregs to cytotoxic exTreg CD4+ T cells 3167

Abstract Description Under conditions of chronic, unresolved inflammation characteristic of atherosclerosis, some regulatory CD4+T cells (Tregs) convert to cytotoxic exTregs. The mechanism driving this conversion is not completely understood. Here we show that autophagy maintains Treg stability by mitigating Endoplasmic reticulum (ER) stress. Unresolved ER-stress in Tregs leads to mitochondrial dysfunction that steers their transition to exTregs. Failure to clear dysfunctional mitochondria ultimately leads to exTreg apoptosis. Tregs defective in autophagy lose suppressive function and gain a pro-inflammatory phenotype characteristic of exTregs. Tregs treated with pro-atherosclerotic stressors like oxidized LDL or IFNγ recapitulate the phenotype of autophagy-defective exTregs. We conclude that the mechanism of Treg to exTreg conversion includes defective autophagy, resultant ER stress and mitochondrial dysfunction. Funding Sources NIH R35 HL145241 NIH P01 HL136275 project 4 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)