Myocardial Milieu Favors Local Differentiation of Regulatory T Cells
| العنوان: | Myocardial Milieu Favors Local Differentiation of Regulatory T Cells |
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| المؤلفون: | Murilo Delgobo, Emil Weiß, DiyaaElDin Ashour, Leon Richter, Lisa Popiolkowski, Panagiota Arampatzi, Verena Stangl, Paula Arias-Loza, Encarnita Mariotti-Ferrandiz, Peter P. Rainer, Antoine-Emmanuel Saliba, Burkhard Ludewig, Ulrich Hofmann, Stefan Frantz, Gustavo Campos Ramos |
| المصدر: | Circulation Research. 132:565-582 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Physiology, Cardiology and Cardiovascular Medicine |
| الوصف: | Background: In the past years, several studies investigated how distinct immune cell subsets affects post–myocardial infarction repair. However, whether and how the tissue environment controls these local immune responses has remained poorly understood. We sought to investigate how antigen-specific T-helper cells differentiate under myocardial milieu’s influence. Methods: We used a transgenic T cell receptor (TCR-M) model and major histocompatibility complex-II tetramers, both myosin-specific, combined with single-cell transcriptomics (single-cell RNA sequencing [scRNA-seq]) and functional phenotyping to elucidate how the antigen-specific CD4 + T cells differentiate in the murine infarcted myocardium and influence tissue repair. Additionally, we transferred proinflammatory versus regulatory predifferentiated TCR-M-cells to dissect how they specially contribute to post–myocardial infarction inflammation. Results: Flow cytometry and scRNA-/TCR-seq analyses revealed that transferred TCR-M cells acquired an induced regulatory phenotype (induced regulatory T cell) in the infarcted myocardium and blunted local inflammation. Myocardial TCR-M cells differentiated into 2 main lineages enriched with either cell activation and profibrotic transcripts (eg, Tgfb1 ) or suppressor immune checkpoints (eg, Pdcd1 ), which we also found in human myocardial tissue. These cells produced high levels of LAP (latency-associated peptide) and inhibited IL-17 (interleukin-17) responses. Endogenous myosin-specific T-helper cells, identified using genetically barcoded tetramers, also accumulated in infarcted hearts and exhibited a regulatory phenotype. Notably, TCR-M cells that were predifferentiated toward a regulatory phenotype in vitro maintained stable in vivo FOXP3 (Forkhead box P3) expression and anti-inflammatory activity whereas T H 17 partially converted toward a regulatory phenotype in the injured myocardium. Overall, the myosin-specific Tregs dampened post–myocardial infarction inflammation, suppressed neighboring T cells, and were associated with improved cardiac function. Conclusions: These findings provide novel evidence that the heart and its draining lymph nodes actively shape local immune responses by promoting the differentiation of antigen-specific Tregs poised with suppressive function. |
| تدمد: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.122.322183 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::9d8fa7f056e314d9d304b9df435c22d7 https://doi.org/10.1161/circresaha.122.322183 |
| رقم الانضمام: | edsair.doi...........9d8fa7f056e314d9d304b9df435c22d7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244571 00097330 |
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| DOI: | 10.1161/circresaha.122.322183 |