Linoleic acid supports mitochondrial function and promotes the survival of human effector memory regulatory T cells

Regulatory T cells (Treg) maintain immune tolerance and their dysfunction contributes to cardiovascular disease (CVD). Among Treg subsets, effector-memory Treg (emTreg) are highly suppressive but metabolically vulnerable, relying on sustained mitochondrial function. We previously found that High Density Lipoproteins (HDL) selectively bind to emTreg and promote their survival. Our new data show that HDL deliver linoleic acid (LA), a dietary omega-6-PUFA, to primary human emTreg, promoting their mitochondrial metabolism and decreasing their apoptosis. LA enhanced emTreg mitochondrial membrane potential and decreased oxidative stress and mitochondrial shrinkage. Mechanistically, we uncovered that blocking ALOX15, which oxidizes LA into bioactive lipids that support mitochondrial integrity, abolished LA protective role. Importantly, we found that this protective pathway is impaired in the context of increased CVD risk. Together, our findings further explain the functional links between HDL and and Treg homeostasis and could open new therapeutic avenues to preserve Treg anti-inflammatory function Overall design: RNA-seq profiling of primary human effector memory regulatory T cells from 3 different healthy subjects treated with PBS (control), HDL, or linoleic acid for 3 h