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Role of CD1d in coxsackievirus B3-induced myocarditis
Sally Huber1, Danielle Sartini, Mark Exley
1Department of Pathology, University of Vermont, Burlington, VT 05446, USA. Sally.Huber@uvm.edu
Insights
Coxsackievirus B3 (CVB3) myocarditis severity depends on CD1d expression. Activated V gamma 4(+) T cells kill infected heart cells via CD1d, highlighting its role in viral myocarditis pathogenesis.
Area of Science:
- Immunology
- Virology
- Cardiology
Background:
- Coxsackievirus B3 (CVB3) infection can cause severe myocarditis.
- CD1d-restricted immunity is typically associated with invariant NKT cells.
- The role of CD1d in CVB3-induced myocarditis pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of CD1d expression in CVB3-induced myocarditis.
- To determine if CD1d-restricted immune cells are involved in the disease.
- To explore the interaction between CVB3 variants, CD1d expression, and T cell activation.
Main Methods:
- Comparative analysis of myocarditis severity in different mouse models (BALB/c, J alpha 281(-/-), CD1d(-/-)).
- In vitro assessment of CD1d expression on cardiac myocytes after infection with different CVB3 variants.
- Flow cytometry to measure V gamma 4(+) T cell activation.
- Cytotoxicity assays using infected myocytes and blocking antibodies (anti-CD1d, anti-MHC class I/II).
Main Results:
- Myocarditis was severe in BALB/c and J alpha 281(-/-) mice but minimal in CD1d(-/-) mice.
- The myocarditic CVB3 (H3) variant increased CD1d expression in cardiac myocytes, unlike the nonmyocarditic variant.
- V gamma 4(+) T cells were activated in H3-infected mice and killed H3-infected myocytes via CD1d-dependent, but MHC-independent, mechanisms.
Conclusions:
- CD1d expression is essential for the pathogenicity of CVB3-induced myocarditis.
- Myocarditic CVB3 variants upregulate CD1d on cardiac myocytes.
- V gamma 4(+) T cells likely recognize CD1d on infected myocytes, contributing to myocarditis development.
Abstract:
The myocarditic (H3) variant of Coxsackievirus B3 (CVB3) causes severe myocarditis in BALB/c mice and BALB/c mice lacking the invariant J alpha 281 gene, but minimal disease in BALB/c CD1d(-/-) animals. This indicates that CD1d expression is important in this disease but does not involve the invariant NKT cell often associated with CD1d-restricted immunity. The H3 variant of the virus increases CD1d expression in vitro in neonatal cardiac myocytes whereas a nonmyocarditic (H310A1) variant does not. V gamma 4(+) T cells show increased activation in both H3-infected BALB/c and J alpha 281(-/-) mice compared with CD1d(-/-) animals. The activated BALB/c V gamma 4(+) T cells from H3-infected mice kill H3-infected BALB/c myocytes and cytotoxicity is blocked with anti-CD1d but not with anti-MHC class I (K(d)/D(d)) or class II (IA/IE) mAbs. In contrast, H3 virus-infected CD1d(-/-) myocytes are not killed. These studies demonstrate that CD1d expression is essential for pathogenicity of CVB3-induced myocarditis, that CD1d expression is increased early after infection in vivo in CD1d(+) mice infected with the myocarditic but not with the nonmyocarditic CVB3 variant, and that V gamma 4(+) T cells, which are known to promote myocarditis susceptibility, appear to recognize CD1d expressed by CVB3-infected myocytes.