Low-self-reactive, circulation-biased blood regulatory T cells sense danger-associated nucleotides to restrain atherosclerosis

Peripheral blood (PB) is the predominant source of regulatory T cells (Tregs) for clinical applications, yet PB Tregs have not been systematically compared with tissue Tregs and their defining properties remain poorly understood. Here we identify a circulation-biased PB Treg population with reduced self-reactivity. Although PB Tregs are less suppressive in vitro, they are hypersensitive to the danger-associated nucleotides ATP and NAD+, linked to a high ARTC2.2/CD38 ratio. ATP/NAD+-triggered apoptotic conversion of PB Tregs promotes macrophage efferocytosis and selectively dampens IFN-{gamma}-driven inflammatory polarization while preserving IL-10-associated programs and enhancing the scavenger receptor Mertk, suggesting that efferocytosis-mediated macrophage reprogramming contributes to lesion control. Consistent with this model, in atherosclerosis-prone mice lacking T cells, PB Treg transfer effectively limits plaque growth and necrotic core formation. We identify an ATP/NAD+-hypersensitive PB Treg fraction in both mice and humans and provide evidence consistent with preferential efferocytosis of this subset within atherosclerotic plaques.