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 () 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 () mice led to marked exacerbation of adverse cardiac remodeling in the mice. Detailed characterization of cardiac regulatory T cells (T cells) demonstrated a time-dependent increase in hearts with altered immunosuppressive profiles. Adoptive transfer of splenic T cells reduced cardiac fibrosis and improved systolic dysfunction in mice with or without lymphocytes. In addition, low-dose interleukin-2 (IL-2)/anti-IL-2 complex (IL-2/c), which specifically induced T cell expansion in vivo, ameliorated cardiac fibrosis and reduced macrophage infiltration and activation in mice. These data contribute to our understanding of HCM and support the use of T cells as a clinically testable therapeutic strategy for cardiac fibrosis in the HCM heart.