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Purification and Transplantation of Myogenic Progenitor Cell Derived Exosomes to Improve Cardiac Function in Duchenne Muscular Dystrophic Mice
Published on: April 10, 2019
Chemotaxis and Immunoregulatory Function of Cardiac γδ T Cells in Dystrophin-Deficient Mice
Cynthia Machado Cascabulho1, Daniela Gois Beghini2, Marcelo Meuser-Batista3
1Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, RJ 21040-900, Brazil; cynthiac@ioc.fiocruz.br.
Insights
Gamma delta T cells migrate to the hearts of Duchenne muscular dystrophy (DMD) mice, offering protection by reducing inflammation and cardiac damage. Their depletion worsens heart pathology in this DMD model.
Area of Science:
- Immunology
- Cardiovascular Research
- Genetics
Background:
- Duchenne muscular dystrophy (DMD) is a severe X-linked genetic disorder causing progressive muscle degeneration.
- The role of gamma delta (γδ) T cells in DMD pathogenesis and cardiac involvement remains largely unexplored.
- Mdx mice serve as a critical model for studying DMD, including cardiac complications.
Purpose of the Study:
- To investigate the presence, phenotype, and function of γδ T cells in the cardiac muscle of mdx mice.
- To determine the impact of γδ T cells on cardiac inflammation and damage in the mdx mouse model.
- To elucidate the potential protective mechanisms of γδ T cells in DMD-associated cardiomyopathy.
Main Methods:
- Analysis of γδ T cell migration to cardiac and skeletal muscles in mdx mice.
- Phenotypic characterization of cardiac γδ T cells using flow cytometry.
- Assessment of chemokine involvement (CCL2, CCL5) in γδ T cell recruitment.
- In vivo depletion of γδ T cells to evaluate their functional role.
- In vitro cytotoxicity assays of purified cardiac γδ T cells.
Main Results:
- γδ T cells were found in the hearts of mdx mice, peaking at 12 weeks, but not in skeletal muscles.
- Cardiac γδ T cells were identified as Vγ1+/CD27+ and produced high levels of IFN-γ.
- Depletion of γδ T cells led to increased cardiac inflammation (CD4+, CD8+, F4/80+ cells) and exacerbated cardiac damage.
- Purified cardiac γδ T cells exhibited perforin/granzyme-dependent cytotoxicity against cardiac macrophages in vitro.
Conclusions:
- γδ T cells play a protective role in the hearts of mdx mice, modulating inflammation and reducing cardiac damage.
- These cells may exert protective effects by selectively eliminating pathogenic cardiac macrophages.
- The findings suggest that γδ T cells are important for the delayed onset of cardiac pathology in DMD.
Abstract:
Duchenne muscular dystrophy (DMD) is a fatal X-linked disorder caused by mutations in the dystrophin gene that lead to degeneration of skeletal and cardiac muscles and to chronic inflammation. Despite the importance of γδ T cells in many diseases, this cellular subpopulation has not been described in DMD patients or in mdx mice, a widely used mouse model for studying DMD. Therefore, in this study, we aimed to evaluate the migration of γδ T cells to the cardiac muscle of mdx mice and to characterize their phenotype and functional activity. We observed no migration of γδ T cells to skeletal muscles, but these cells were found in the hearts of mdx mice during the study period, reaching a peak in 12-wk-old mice. These cells migrate primarily owing to CCL2 and CCL5 chemokines produced by cardiac tissue, and they are Vγ1+/CD27+ and thus produce high levels of IFN-γ. In vivo depletion of the γδ T cells revealed γδ T cell-dependent cardiac inflammatory immunoregulation, with increased numbers of CD3+CD4+, CD3+CD8+, and, in particular, F4/80+ cells in the heart and increased cardiac damage in mdx mice. We also observed in vitro that purified cardiac Γδ T cells are cytotoxic against adherent endomysial cardiac cells, mostly macrophages, but not against peritoneal cells, in a perforin/granzyme-dependent manner. Our present data indicate that γδ T cells exert protective effects on the hearts of mdx mice, possibly by selectively killing pathogenic macrophages, and this function may be important for the late onset of cardiac damage in DMD.
