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CITE-seq of cardiac CD45+ leukocytes in mice with myocardial infarction and NK cell depletion

ABSTRACT: Myocardial infarction triggers an inflammatory response which plays a crucial role in repair and remodelling of the infarcted heart. In this study we examined the role of Natural Killer cells (NK cells), a specific type of inflammatory cells, in controlling the inflammatory response and cardiac repair after myocardial infarction. To assess effects on local inflammation, we used single-cell RNA-seq and CITE-seq to profile cardiac CD45+ leukocytes in infarcted mice with or without NK cell depletion. Biological replicates from the different experimental conditions were pooled using cell hashing as follows: hashtag 1 to 5 control mice; hashtags 6 to 10: NK-depleted mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE317004 | GEO | 2026/02/10

REPOSITORIES: GEO

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Project description:Myocardial infarction (MI) is a sterile inflammatory condition that results in the activation of T- cells targeting cardiac antigens. T-cells have been shown to contribute to reparative and maladaptive remodeling post-MI. However, the differentiation trajectories and in situ activity of heart-specific CD4+T cells and the effect of distinct T-cell phenotypes on MI repair remains poorly understood. Herein, we combined T-cell receptor transgenic models and tetramer staining targeting myocardial protein with single-cell transcriptomics (scRNAseq) and functional phenotyping to elucidate how the myosin-specific CD4+ T cells (TCR-M) differentiate in the murine infarcted myocardium and influence tissue repair. Furthermore, we transferred pro-inflammatory versus regulatory pre-differentiated heart-specific T-cells to dissect how they differentially regulate post-myocardial infarction (MI) inflammation. Flow cytometry and scRNAseq findings reveled that transferred TCR-M cells acquired an induced regulatory phenotype (iTreg) in the infarcted myocardium and blunt local inflammation. Myocardial TCR-M cells differentiated into two main lineages enriched with cell activation and pro-fibrotic transcripts (e.g. Tgfb1) or with suppressor immune checkpoints (e.g. Pdcd1), which we also found in human myocardial tissue. These cells produced high levels of latency-associated peptide (LAP) and inhibited interleukine-17 (IL-17) responses. Tetramer staining further identified endogenous myosin-specific T-cells that acquired a regulatory phenotype in the heart post-MI. Notably, TCR-M cells that were pre-differentiated in vitro towards a regulatory phenotype maintained a stable in vivo FOXP3 expression and anti-inflammatory activity whereas TH17 partially converted towards a regulatory phenotype in the injured myocardium, which was associated to blunted myocardial inflammation. Moreover, myocardial scar of Treg TCR-M transferred mice showed blunted inflammatory transcripts and enrichment for growth factors supporting fibroblasts and endothelial cells.

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CITE-seq of cardiac CD45+ leukocytes in mice with myocardial infarction and NK cell depletion

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