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

Abstract 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-γ–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. Competing Interest Statement The authors have declared no competing interest.