Journal of molecular and cellular cardiology · 2025
Phenotypes and mechanisms of dysfunctional cardiac T-lymphocytes in dilated cardiomyopathy patients.
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Angelotti Austin, Ponnusamy Thiruvelselvan, Kumar Vinay, Passarelli Gianna V, Malysz Jozef, Mahesh Balakrishnan, Soleimani Behzad, Bradley Elisa A, Bansal Shyam S
Аннотация
BACKGROUND: Dilated cardiomyopathy (DCM) is characterized by increased infiltration and activation of the innate immune system, including neutrophils, monocytes/macrophages, and dendritic cells. However, the phenotypic profile of cardiac CD3+ T-cells and its CD4+ and CD8+ subsets have not been characterized in DCM patients.
METHODS: We studied phenotypic signatures of T-cell subsets by analyzing publicly available single-cell and single-nuclear transcriptomic datasets from control and failing hearts of DCM patients.
RESULTS: Our analysis revealed increased cardiac infiltration of CD3+ T-cells in DCM patients with transcriptomic signatures indicating antigenic activation, T-cell exhaustion, diminished oxidative phosphorylation, and elevated TNF/NFκB and profibrotic TGF signaling. Among T-cell subsets, both CD4+ and CD8+ T-cells were found to be highly proliferative (increased G2M) and activated. Transcription profiling demonstrated four phenotypically different subsets for both CD8+ and CD4+ T-cells, however, only CD4+ T-cell subsets, regulatory T-cells and tissue resident memory (TRM) CD4+ T-cells, were significantly increased. Importantly, TRM cells displayed decreased expression of classical egress markers, such as CCR7, SELL, and MAL, and increased pro-inflammatory and pro-fibrotic signaling. We also observed increased estrogen receptor (ER)α expressing (with amplified ERα signaling) cardiac CD4+ T-cells which directly correlated with systolic dysfunction and mediated their pro-fibrotic effects in DCM patients.
CONCLUSION: Here we demonstrate for the first time, an "activated phenotype" with increased pro-inflammatory and profibrotic signaling in cardiac CD3+ T-cells and its CD4+ helper T-cell subset in DCM hearts. Notably, increased ERα signaling provide novel avenues for targeted immunomodulatory therapies to modify DCM progression.
METHODS: We studied phenotypic signatures of T-cell subsets by analyzing publicly available single-cell and single-nuclear transcriptomic datasets from control and failing hearts of DCM patients.
RESULTS: Our analysis revealed increased cardiac infiltration of CD3+ T-cells in DCM patients with transcriptomic signatures indicating antigenic activation, T-cell exhaustion, diminished oxidative phosphorylation, and elevated TNF/NFκB and profibrotic TGF signaling. Among T-cell subsets, both CD4+ and CD8+ T-cells were found to be highly proliferative (increased G2M) and activated. Transcription profiling demonstrated four phenotypically different subsets for both CD8+ and CD4+ T-cells, however, only CD4+ T-cell subsets, regulatory T-cells and tissue resident memory (TRM) CD4+ T-cells, were significantly increased. Importantly, TRM cells displayed decreased expression of classical egress markers, such as CCR7, SELL, and MAL, and increased pro-inflammatory and pro-fibrotic signaling. We also observed increased estrogen receptor (ER)α expressing (with amplified ERα signaling) cardiac CD4+ T-cells which directly correlated with systolic dysfunction and mediated their pro-fibrotic effects in DCM patients.
CONCLUSION: Here we demonstrate for the first time, an "activated phenotype" with increased pro-inflammatory and profibrotic signaling in cardiac CD3+ T-cells and its CD4+ helper T-cell subset in DCM hearts. Notably, increased ERα signaling provide novel avenues for targeted immunomodulatory therapies to modify DCM progression.