Biology subjects

Ramos, G. C.

Publications and source records attributed to Ramos, G. C..

3 recordsLinked to original sources

bioRxiv2025

CD4+ T cells fuel the Duchenne cardiomyopathy

Duchenne muscular dystrophy (DMD) is a X-linked genetic disorder, in which cardiomyopathy represents a major cause of mortality. Although myocardial inflammation and fibrosis are hallmarks of the disease, the role of adaptive immunity in cardiac pathology remains poorly defined. Using the Mdx mouse model, we demonstrate that T and B lymphocytes accumulate in the heart and that activation occurs in heart-draining lymph nodes at an early disease stage. Mdx mice lacking adaptive immunity (Mdx-Scid) were protected from myocardial fibrosis and hypertrophic remodeling. Single-cell RNA sequencing revealed expansion of an inflammatory, matrisome-associated macrophage subset in Mdx but not Mdx-Scid hearts. Genetic deficiency or depletion of CD4+ T cells reduced left ventricular fibrosis and preserved systolic function. Moreover, adoptive transfer of T cells von Mdx mice induced myocardial fibrosis and dysfunction in healthy recipients. Our results identify autoreactive CD4+ T cells as key drivers of DMD-associated cardiomyopathy and suggest targeted modulation of adaptive immune responses as a potential therapeutic approach in DMD.

immunology↗

bioRxiv2024

Identification of a novel myosin antigen activating CD8+ T cells in C57BL/6 mice

Heart-specific T cells play important roles in myocardial diseases, including myocarditis, myocardial infarction, and heart failure. However, only few cardiac antigens and their respective specific T cell receptors (TCRs) have been validated so far. Therefore, we sought to identify new cardiac T cell epitopes in C57BL/6 mice and to characterize the specific TCRs. Antigen mapping of myosin heavy chain alpha (MYHCA) led to the identification of a 9-mer epitope (MYHCA724-732) recognized by CD8+ T cells. Single-cell TCR sequencing (scTCR-seq) analysis of MYHCA-stimulated CD8+ T cells enabled the identification of distinct TCRs enriched on specific T cells. Selected TCRs inferred from scTCR-seq data were then expressed on reporter cell lines and functionally validated. Our study expands the toolkit required to study heart-directed immune responses by revealing a new cardiac antigen and specific TCRs. These tools will enable in vivo characterization of myosin-specific CD8+ T cells in murine models of myocardial diseases.

immunology↗

bioRxiv2022

Rapid differentiation of regulatory CD4+ T cells in the infarcted myocardium blunts in situ inflammation

BackgroundMyocardial infarction (MI) is a sterile inflammatory condition associated with tissue injury that results in the activation of T helper cell targeting cardiac antigens. However, the differentiation trajectories and in situ activity of heart-specific CD4+T cells activated in the MI context remain poorly understood. MethodsHerein, we combined T-cell receptor transgenic models targeting myocardial protein, single-cell transcriptomics, and functional phenotyping to elucidate how the myosin-specific CD4+ T cells (TCR-M) differentiate in the murine infarcted myocardium and ultimately influence tissue repair. Furthermore, we adoptively transferred heart-specific T-cells that were pre-differentiated in vitro towards pro-inflammatory versus regulatory phenotypic states to dissect how they differentially regulate post-myocardial infarction (MI) inflammation. ResultsFlow cytometry and single-cell transcriptomics findings reveled that transferred TCR-M cells rapidly 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. 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 when adoptively transferred prior to MI induction. In contrast, TCR-M cells that were pre-differentiated in vitro towards a pro-inflammatory TH17 phenotype were partially converted towards a regulatory phenotype in the injured myocardium and blunted myocardial inflammation. ConclusionsThese findings reveal that the myocardial milieu provides a suitable environment for iTreg differentiation and reveals novels mechanisms by which the healing myocardium shapes local immunological processes.

immunology↗