Regression of atherosclerosis is an important clinical goal; however, the pathways that mediate atherosclerotic inflammation and reversal of plaques are poorly understood. Regulatory T cells (Tregs) are atheroprotective, yet the numbers of these immunosuppressive cells decrease with disease progression, and whether they contribute to atherosclerosis regression is unknown. This study aimed to investigate Tregs’ roles in the resolution of atherosclerotic inflammation, tissue remodeling, and plaque contraction during atherosclerosis regression.

Single-cell RNA-sequencing of plaque immune cells revealed that unlike Tregs from progressing plaques that expressed natural Tregs markers derived from the thymus, Tregs in regressing plaques lacked Nrp1 expression, suggesting that they are induced in the periphery during lipid-lowering therapy. Morphometric analyses revealed that Treg depletion blocked plaque remodeling and contraction, and impaired inflammation resolution hallmarks, including dampening of the T helper 1 response, alternative activation of macrophages, efferocytosis, and upregulation of specialized pro-resolving lipid mediators.

Our data establish essential roles for Tregs in resolving atherosclerotic cardiovascular disease and provide mechanistic insight into the pathways governing plaque remodeling and disease regression. Our study in mice supports further investigation into strategies to enhance Treg numbers and functions in atherosclerotic plaques as a mechanism for promoting tissue repair and inflammation resolution.