Regulatory T cells attenuate chronic inflammation and cardiac fibrosis in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart muscle disorder. Although the biophysical mechanisms by which gene variants in sarcomeric proteins disrupt cardiomyocyte function are largely understood, the cellular and molecular pathways leading to the complex, variable, and adverse remodeling of the non-myocyte compartment are unexplained. Here, we report that postmortem and explanted human HCM hearts exhibited chronic focal leukocyte infiltration and prominent activation of immune cells. Gene set enrichment analysis (GSEA) revealed that active immune responses were present in the mid- and late-stage HCM human hearts and in mouse hearts from several HCM mouse models. The alpha cardiac actin 1-E99K (Actc1^E99K) HCM mouse model was selected for the study because it closely recapitulates the features of progressive remodeling and fibrosis seen in advanced disease in patients. Genetic depletion of lymphocytes in recombination activating gene 1-knockout (Rag-1^KO) mice led to marked exacerbation of adverse cardiac remodeling in the Actc1^E99K mice. Detailed characterization of cardiac regulatory T cells (T_reg cells) demonstrated a time-dependent increase in Actc1^E99K hearts with altered immunosuppressive profiles. Adoptive transfer of splenic T_reg cells reduced cardiac fibrosis and improved systolic dysfunction in Actc1^E99K mice with or without lymphocytes. In addition, low-dose interleukin-2 (IL-2)/anti-IL-2 complex (IL-2/c), which specifically induced T_reg cell expansion in vivo, ameliorated cardiac fibrosis and reduced macrophage infiltration and activation in Actc1^E99K mice. These data contribute to our understanding of HCM and support the use of T_reg cells as a clinically testable therapeutic strategy for cardiac fibrosis in the HCM heart.