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Gene expression profile of myosin-specific CD4+ T-cells activated after myocardial infarction

ABSTRACT: Pathological expansion of self-reactive T cells is a hallmark of autoimmune diseases. Notwith-standing, T cell autoreactivity can also benefit self-maintenance and foster tissue repair. Herein, we investigated whether heart-specific T cells exert salutary or detrimental effects in the context of the post myocardial infarction (MI) healing process in mice, and whether the findings can be translated to humans. Transferred cardiac-myosin-specific CD4+ T cells (TCR-M) selectively accumulate in the myocardium and mediastinal lymph nodes (med-LNs) of infarcted mice. TCR-M cells activated in the MI-context acquire a Foxp3+ regulatory phenotype, exhibit a distinct gene expression profile enriched with growth factors, and promote cardioprotection. Massive parallel sequencing of T cell receptors revealed that CD4+ T cells infiltrating the infarcted myo-cardium display a unique repertoire signature with skewed diversity and dominated by a limited set of expanded clones - hallmarks of antigen-specific responses. CD4+ Foxp3+ cells were also detected in myocardial biopsies obtained from patients who suffered MI, especially in associa-tion with the granulation tissue (i.e., healing phase). Noninvasive positron emission tomogra-phy/computed tomography (PET/CT) imaging using a CXCR4 radioligand revealed that MI pa-tients display enlarged med-LNs with increased T cellularity. Alterations in the med-LN corre-lated with infarct size and cardiac function. Taken together, these results provide strong evidence that the MI-context induces protective T cell autoimmunity in mice, and confirm the existence of an analogous physiological heart/med-LN/T cell axis in MI patients, which offers translational potential.

ORGANISM(S): Mus musculus

PROVIDER: GSE116569 | GEO | 2019/08/14

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.