Abstract P3069: ScRNA-seq And Flow Cytometry Based Analysis Reveals That Chronic Heart Failure Associates With Enhanced Activation And Clonal Expansion Of T Cells With Predictive Autoreactive Capacity

Abstract

Background: Heart failure (HF) is marked by adverse remodelling and chronic inflammation causing impaired function of the heart and poor prognosis. While much is known about the immune response immediately after MI, little is known of the role of the immune system in chronic HF. Our aim is to elucidate the response of T cells to HF. Methods and Results: In a pilot study assessing healthy controls (HC) and HF patients (n=16), scRNA-seq showed an enhanced T cell activation profile in HF patients. A confirmation cohort of n=180 HC and HF patients using flow cytometry of immune cells confirmed an increase of T cell memory/effector cells (HF=65%, HC=53% activated T cells). Correspondingly, circulating antigen presenting cells showed augmented inflammatory profiles (ICAM-1, TREM-1). Given that T cells showed strong activation profiles in HF patients, we investigated whether T cells are preferentially clonally expanded in the same patients. Bulk T cell receptor (TCR) sequencing revealed that TCR diversity was significantly reduced (p=0.03) along with clonal expansion of T cells in HF patients. To assess what T cells might be targeting, we utilized epitope prediction tools to identify 22 unique human-derived epitopes found only in HF patients. ScRNA-seq of CD45+ sorted cardiac-derived and circulating cells of the same HF patient (N=1) versus healthy controls (n=4) showed clonal expansion of TCRs in the cardiac tissue and blood in HF and epitope prediction confirmed epitopes found in bulk TCR sequencing. When modelling this in mice, a scRNA-seq post-MI time course also found an accumulation of specifically pro-inflammatory (Th17) T cells in the heart at days 14, 28 and 48 post-MI. To assess the impact of immune dysregulation in HF on cardiac cells, we cultured the secretome of HF or HC immune cells with endothelial cells and found decreased viability of endothelial cells and increased monocyte adhesion to stimulated endothelial cells (p=0.005). Conclusion: This study suggests that chronic HF may drive persistent T cell activation and clonal expansion, with potential cardiac-relevant autoimmune implications causing or promoting adverse remodelling. These data also provide additional insights for therapeutic cardio-immunological interventions.