The acute immune response after an Myocardial infarction (MI) is well-studied, while little is known about the chronic response in heart failure (HF) patients, thus we aim to elucidate the chronic T-cell response.
Assessing healthy controls (HC) and HF patients (n=16) via scRNA-seq showed an enhanced T-cell activation profile in HF combined with an increased capacity for antigen-presentation on monocytes. Flow cytometric analysis of peripheral blood from n=172 HC and HF patients confirmed this increase of T memory/effector cells (HF=65%, HC=53% activated T-cells) and a reduction of the naïve T-cell compartment in HF. Correspondingly, APCs showed a higher immune stimulatory profile (e.g. HLA-DR, ICAM-1, TREM-1). T helper subsets of HF patients also expressed elevated levels of the homing marker CCR5, especially within Th17 and Th22 cells. Immune secretome analysis supports these findings through significantly increased serum levels of sICAM-1, IL6 and TNFRI.
The strong T-cell activation profile in HF compelled us to investigate, whether T-cells clonally expanded in these patients. Bulk TCR sequencing revealed that TCR diversity was significantly reduced (p=0.03) while TCR clones were expanded in HF. To assess what these T-cells might be targeting, we utilized epitope prediction modelling to identify 22 unique human-derived epitopes found only in HF.
Time course assessment of immunoregulatory kinetics post-myocardial infarction in mice via scRNA-seq from days 0 to 28 post-infarct revealed that chemoattractants changed between acute phase (d1-d3 post-MI, Ccl12 and Ccl2) and the late phase response (d14-d28 post-MI, Ccl4, Cxcl10, Cx3cl1). These molecules, in conjunction with the enhanced expression levels of CCR5 on HF derived T-cells, fit the observed infiltration kinetic of T-cells which increase in numbers again in the late phase after MI.
This study suggests that chronic HF may drive persistent T-cell activation and clonal expansion, with potential autoimmune implications promoting adverse remodelling.