Abstract
Under conditions of chronic unresolved inflammation characteristic of atherosclerosis, regulatory CD4+ T cells (Tregs) become unstable and convert to cytotoxic exTregs. The mechanism driving this conversion in humans is unclear. Here, we show unresolved endoplasmic reticulum (ER) stress as a key factor driving Treg instability. Human exTregs undergo ER stress and consequent mitochondrial dysfunction that remains unchecked due to defective mitophagy. Integrated stress response (ISR), a pathway that can trigger inflammatory signaling, is also upregulated in exTregs. exTregs are highly apoptotic and are more susceptible to stress-mediated cellular dysfunction due to their senescent state. In a phenotype reminiscent of exTregs, Tregs from coronary artery disease (CAD) patients show high ER stress and mitochondrial depolarization. This is further exacerbated in CD4+ T cells residing in atherosclerotic plaques. Pro-atherosclerotic stressors such as oxLDL and interferon-γ induce ER stress and mitochondrial dysfunction in Tregs in vitro. We conclude that the maladaptive inflammatory environment in atherosclerosis triggers ER stress and mitochondrial dysfunction, contributing to Treg instability in CAD.