Human, mouse scRNA-seq and flow cytometry data in ischemic heart failure models predict immune cell activation signatures with altered endothelial cell cross talk

• Published in: European heart journal Vol. 43; no. Supplement_2
• Main Authors: Merten, M, Rasper, T, Cremer, S, Schuhmacher, B, Tombor, L, Zeiher, A M, Hoffmann, J, Abplanalp, W T, Dimmeler, S
• Format: Journal Article
• Language: English
• Published: 03-10-2022
• ISSN: 0195-668X; 1522-9645
• DOI: 10.1093/eurheartj/ehac544.2965

Abstract

Chronic ischemic Heart Failure (HF) with reduced ejection fraction is marked by adverse remodelling and sustained inflammation. The effects of monocytes and T cells in early state immune responses after myocardial infarction are known, to date their role in progression and maintenance of chronic HF remains elusive.
Single cell RNA sequencing of peripheral immune cells from healthy and HF donors revealed a significant increase of the antigen presentation (i.e. HLA-DRB5) and co-stimulatory molecules (i.e. ICAM-1) on monocytes, while the elevation of the T effector memory population in HF patients shows enhanced T cell activation. Subsequent flow cytometry validation in 55 healthy and 110 HF patients confirmed that HF derived monocytes have elevated levels of HLA-DRB5 predicts increased ICAM-1 and TREM-1 (p<0.0001 for both), indicating enhanced T cell activation capacity. In addition, the activated fraction of both CD4+ and CD8+ T cells, including central memory, effector memory and TEMRA cells, is significantly enriched in the HF patients (p<0.0001 for both) with reduction of the naïve T cells. T cell receptor (TCR) sequencing of age matched healthy and HF donors showed an increase in the relative TCR clonality in HF patients, indicating an expansion of the circulating T cells.
ScRNA-seq murine myocardial infarction (MI) time course data (day (d) 0/1/3/7/14/28/48 post-MI), found a progressive increase in Th17 cells and activated CD8+ T cells in the cardiac tissue at d48 (2.8x-, and 2.7x-fold, respectively) relative to d0. The T cell imbalance was marked by loss of immunosuppressive markers such as Lef1 (p=2e-30) in T cell clusters primarily populated by d48 relative to d0.
Mechanistically the downstream effects of the immune cell activation were analysed in the serum of HF patients, where increased levels of sICAM-1, IL-6 and TNFRI levels (1.75x-, 5.30x-, 2.63x-fold, respectively) could be detected. Furthermore, treatment of endothelial cells with the conditioning media from HF-immune cells induced capability to adhere with monocytes in a co-culture system but also decreased the checkpoint inhibitor molecule PD-L1, a known blocker of autoreactive T cells.
These data link HF with enhanced monocyte and T cell activation as well as T cell clonal expansion, along with increased T cell numbers in mouse hearts post-MI. These data suggest HF is may drive impaired resolution of inflammation in cardiac tissue and facilitate adverse remodelling and cardiac damage. Further studies will assess the specific role of chronic monocyte and T cell activation in the progression of heart failure.
Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DFG -Deutsche ForschungsgemeinschaftDZHK -Deutsches Zentrum für Herzkreislauferkrankungen