Abstract

Background: Chronic heart failure (HF) is characterized by adverse remodeling and persistent inflammation, leading to impaired heart function and poor prognosis. While the acute immune response post-myocardial infarction (MI) is well-studied, the role of the immune system in chronic HF remains unclear. This study aims to elucidate the response of T cells to HF. Methods and Results: In a cohort of 188 HF patients and healthy controls (HC), flow cytometry of peripheral blood revealed an increase in T cell memory/effector cells (HF=65%, HC=53% activated T cells) and a reduction in naïve T cells in HF patients. Additionally, antigen-presenting cells (APCs) displayed a higher immune stimulatory profile (e.g., HLA-DR, ICAM-1, TREM-1). Immune secretome analysis supported the chronic inflammatory state with significantly elevated serum levels of sICAM-1, IL6, and TNFRI in HF patients. Phenotyping of peripheral blood T cells showed a decline in T central memory cells (TCM) and an increase in CD4+ Th17 and CD8+ T effector memory cells in HF patients compared to healthy controls. This decline in TCM cells and the increased expression of the homing marker CCR5 on T cell subsets were associated with poor prognosis in HF. T cell receptor (TCR) sequencing revealed reduced TCR diversity (p=0.03) and clonal expansion in circulating and cardiac T cells of HF patients. Epitope prediction modeling identified 22 unique human-derived epitopes specific to HF, suggesting potential autoreactivity. Single-cell RNA sequencing (scRNA-seq) of CD45+ sorted cardiac and circulating cells confirmed clonal TCR expansion in the heart and blood of HF patients. Post-MI mouse models demonstrated an accumulation of pro-inflammatory Th17 T cells in the heart at days 14, 28, and 48, with later time points showing more pronounced pro-inflammatory profiles. Conclusion: Chronic HF is associated with persistent T cell activation and clonal expansion, potentially contributing to adverse remodeling and poor prognosis through autoimmune mechanisms. These findings provide insights for therapeutic cardio-immunological interventions targeting T cell responses in HF.