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-2_LD) selectively increases regulatory T (T_reg) cell numbers in patients with coronary artery disease. Here we combine single-cell transcriptomics and T cell receptor analyses and show that IL-2_LD clonally expands effector T_reg cells in patients with acute coronary syndromes. The clonally expanded T_reg cells upregulate key immunosuppressive and metabolic pathways and show an increased number of predicted ligand-receptor interactions. These T_reg 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-2_LD. We identify BACH2 as a repressor of the T_reg effector program. However, BACH2-mediated regulation is bypassed with IL-2_LD. Overall, these results lend insight into the IL-2-driven clonal expansion program in human T_reg cells, with important therapeutic implications for patients with cardiovascular and other immune-mediated diseases.