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Apoptosis in coxsackievirus B3-induced myocarditis and dilated cardiomyopathy
S A Huber1, R C Budd, K Rossner
1Department of Pathology, University of Vermont, Burlington 05405, USA. shuber(a)salus.uvm.edu
Insights
Group B coxsackievirus infection can cause heart disease by stimulating autoimmune T cells. Gamma-delta T cells protect the heart by eliminating disease-promoting Th2 cells, thus preventing myocarditis.
Area of Science:
- Immunology
- Cardiology
- Virology
Background:
- Group B coxsackieviruses (CVB) infect the myocardium, leading to myocarditis and dilated cardiomyopathy.
- However, not all CVB infections result in cardiac disease, suggesting immune system modulation plays a role.
- Autoimmune T cell responses to cardiac antigens are implicated in CVB-induced myocyte necrosis and cardiomyopathy.
Purpose of the Study:
- To investigate the role of T cell subsets in CVB-induced myocarditis.
- To elucidate the mechanism by which gamma-delta T cells influence autoimmune responses in the heart.
- To understand how immune modulation impacts disease outcome following CVB infection.
Main Methods:
- Utilized a mouse model of CVB infection.
- Analyzed T helper 1 (Th1) and T helper 2 (Th2) cell responses.
- Investigated the function of gamma-delta T cell receptor (gamma delta +) lymphocytes in modulating T cell populations.
- Examined cell-cell interactions and Fas:FasL pathways in immune modulation.
Main Results:
- Pathogenic autoimmunity induction depends on CD4+ Th1 cells, while Th2 cells promote resistance.
- Gamma-delta + lymphocytes are crucial for maintaining a dominant Th1 response phenotype.
- Gamma-delta + lymphocytes selectively lyse CD4+ Th2 cells, but not Th1 cells, through direct cell contact, likely via Fas:FasL interaction.
- These findings reveal a novel immune modulation mechanism influencing cytokine responses in vivo.
Conclusions:
- Gamma-delta T cells play a critical protective role in CVB-induced myocarditis by eliminating pathogenic Th2 cells.
- The selective lysis of Th2 cells by gamma-delta T cells represents a novel mechanism for immune regulation in viral heart disease.
- Understanding this immune crosstalk is vital for developing therapeutic strategies against CVB-induced cardiac pathologies.
Abstract:
Group B coxsackieviruses (CVB), which infect the myocardium, cause myocarditis and dilated cardiomyopathy. However, not all infections of the myocardium result in disease. In the mouse model, CVB infection stimulates autoimmune T cell response to cardiac antigens, and these autoimmune effectors cause myocyte necrosis and cardiomyopathy. Induction of pathogenic autoimmunity depends upon CD4+ Th1 (interferon-gamma positive) cells while Th2 (IL-4 positive) cell responses promote disease resistance. T lymphocytes expressing the gamma-delta T cell receptor (gamma delta +) constitute up to 12% of the inflammatory cells in the heart and are crucial to maintaining a dominant Th1 response phenotype. gamma delta + lymphocytes modulate T cell responses by selectively lysing CD4+ Th2 cells. Th1 cells are not killed by gamma delta + cells. Lysis requires direct cell:cell interaction between the gamma delta + cell and CD4+ Th2 target and is most likely mediated through Fas:FasL interaction. These studies demonstrate a novel mechanism for immune modulation of cytokine responses in vivo.