Low-dose interleukin-2 induces clonal expansion of BACH2-repressed effector regulatory T cells following acute coronary syndrome

Targeting inflammation in atherosclerotic cardiovascular disease remains a major unmet need. Low-dose interleukin-2 (IL-2LD) selectively increases regulatory T (Treg) cell numbers in patients with coronary artery disease. Here we combine single-cell transcriptomics and T cell receptor analyses and show that IL-2LD clonally expands effector Treg cells in patients with acute coronary syndromes. The clonally expanded Treg cells upregulate key immunosuppressive and metabolic pathways and show an increased number of predicted ligand–receptor interactions. These Treg cells also display similar predicted antigen specificities, which cluster with published sequences specific to atherosclerotic cardiovascular disease. By tracking the T cell receptors of single cells over time, we identify an inflammatory polarization of the T cell compartment after myocardial infarction, which is restrained by IL-2LD. We identify BACH2 as a repressor of the Treg effector program. However, BACH2-mediated regulation is bypassed with IL-2LD. Overall, these results lend insight into the IL-2-driven clonal expansion program in human Treg cells, with important therapeutic implications for patients with cardiovascular and other immune-mediated diseases. By integrating single-cell transcriptomics and T cell receptor repertoire analyses of regulatory T (Treg) cells in a cohort of patients with acute coronary syndrome from the LILACS trial, Case et al. show that low-dose interleukin-2 clonally expands Treg cells and maintains their suppressive program by bypassing BACH2 downregulation.