Coxsackievirus B3 (CVB3) infection causes myocarditis and dilated cardiomyopathy. The pathogenic mechanisms of the disease are complex. Myocarditis susceptibility correlates with activation of T cells expressing the Vgamma4 T cell receptor (TCR), CD4+ Thi (IFNgamma+) and CD8+alphabeta TCR+ autoimmune cytolytic T cells (CTL). Myocarditis resistance correlates to activation of Vgamma1+ and CD4+Th2 (IL4+) cells, and the absence of autoimmune CD8+alphabeta TCR+ effectors. Vgamma4+ cells kill both CVB3-infected myocytes and CD4+Th2 cells in vitro, and comprise up to 50% of the inflammatory T cells in the heart. CD8+alphabeta TCR+ autoimmune CTL kill uninfected but not virus-infected myocytes, and are the second most populous inflammatory cells in myocarditis. Since both Vgamma4+ and CD8+alphabeta TCR+ cells are cytolytic to cardiac myocytes in vitro, either or both populations might contribute to cardiac injury in vivo. Vgamma4+ cells recognize CD1, a major histocompatibility complex (MHC) class I-like molecule which normally presents hydrophobic lipid or peptide antigens. The autoimmune CD8+alphabeta TCR+ cells recognize antigen presented by classical MHC class I molecules. The overall goal of this application is to define the relative contributions of Vgamma4+ and CD8+alphabeta TCR+ cells to myocarditis in vivo, and determine whether Vgamma4+ cells facilitate CD8+alphabeta TCR+ cell activation by promoting CD4+ Th1 cell responses.
The Specific Aims are to: 1) determine the relative importance of Vgamma4+ cell mediated killing of myocytes or modulation of CD4+ cell phenotype and activation of CD8+alphabeta TCR+ CTL in myocarditis; 2) determine CD1d expression in pathogenic versus non-pathogenic CVB3 infections and the role for lipid or peptide antigens in the CD1d-restricted Vgamma4+ T cell response; and 3) determine whether Vgamma4+ cells kill CD4+Th2 cells through CD1 -restricted responses.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058583-07
Application #
6747911
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Massicot-Fisher, Judith
Project Start
1998-04-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
7
Fiscal Year
2004
Total Cost
$151,500
Indirect Cost
Name
University of Vermont & St Agric College
Department
Pathology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Huber, S (2008) Host immune responses to coxsackievirus B3. Curr Top Microbiol Immunol 323:199-221
Huber, Sally A; Feldman, Arthur M; Sartini, Danielle (2006) Coxsackievirus B3 induces T regulatory cells, which inhibit cardiomyopathy in tumor necrosis factor-alpha transgenic mice. Circ Res 99:1109-16
Huber, S A (2006) CD1d expression on hemopoietic cells promotes CD4+ Th1 response in coxsackievirus B3 induced myocarditis. Virology 352:226-36
Huber, Sally; Song, Wen-Chao; Sartini, Danielle (2006) Decay-accelerating factor (CD55) promotes CD1d expression and Vgamma4+ T-cell activation in coxsackievirus B3-induced myocarditis. Viral Immunol 19:156-66
Huber, Sally; Dohrman, Austin; Sartini, Danielle et al. (2006) Reduced myocarditis following Coxsackievirus infection in cellular FLICE inhibitory protein--long form-transgenic mice. Immunology 119:541-50
Huber, S A; Sartini, D (2005) Roles of tumor necrosis factor alpha (TNF-alpha) and the p55 TNF receptor in CD1d induction and coxsackievirus B3-induced myocarditis. J Virol 79:2659-65
Huber, Sally (2004) T cells in coxsackievirus-induced myocarditis. Viral Immunol 17:152-64
Gauntt, Charles; Huber, Sally (2003) Coxsackievirus experimental heart diseases. Front Biosci 8:e23-35
Huber, Sally; Sartini, Danielle; Exley, Mark (2003) Role of CD1d in coxsackievirus B3-induced myocarditis. J Immunol 170:3147-53
Roessner, Karen; Wolfe, Julie; Shi, Cuixia et al. (2003) High expression of Fas ligand by synovial fluid-derived gamma delta T cells in Lyme arthritis. J Immunol 170:2702-10

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