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.