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Journal of Virology, July 2001, p. 5860-5869, Vol. 75, No. 13
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.13.5860-5869.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Cytokine Production by Vgamma +-T-Cell Subsets Is an Important Factor Determining CD4+-Th-Cell Phenotype and Susceptibility of BALB/c Mice to Coxsackievirus B3-Induced Myocarditis

Sally A. Huber,1,* Danielle Graveline,1 Willi K. Born,2 and Rebecca L. O'Brien2

Department of Pathology, University of Vermont, Burlington, Vermont,1 and Department of Immunology, National Jewish Medical and Research Center, Denver, Colorado2

Received 24 January 2001/Accepted 3 April 2001

Two coxsackievirus B3 (CVB3) variants (H3 and H310A1) differ by a single amino acid mutation in the VP2 capsid protein. H3 induces severe myocarditis in BALB/c mice, but H310A1 is amyocarditic. Infection with H3, but not H310A1, preferentially activates Vgamma 4 Vdelta 4 cells, which are strongly positive for gamma interferon (IFN-gamma ), whereas Vgamma 1 Vdelta 4 cells are increased in both H3 and H310A1 virus-infected animals. Depletion of Vgamma 1+ cells using monoclonal anti-Vgamma 1 antibody enhanced myocarditis and CD4+-, IFN-gamma +-cell responses in both H3- and H310A1-infected mice yet decreased the CD4+-, IL-4+-cell response. Depleting Vgamma 4+ cells suppressed myocarditis and reduced CD4+ IFN-gamma + cells but increased CD4+ IL-4+ T cells. The role of cytokine production by Vgamma 1+ and Vgamma 4+ T cells was investigated by adoptively transferring these cells isolated from H3-infected BALB/c Stat4 knockout (Stat4ko) (defective in IFN-gamma expression) or BALB/c Stat6ko (defective in IL-4 expression) mice into H3 virus-infected wild-type BALB/c recipients. Vgamma 4 and Vgamma 1+ T cells from Stat4ko mice expressed IL-4 but no or minimal IFN-gamma , whereas these cell populations derived from Stat6ko mice expressed IFN-gamma but no IL-4. Stat4ko Vgamma 1+ cells (IL-4+) suppress myocarditis. Stat6ko Vgamma 1+ cells (IFN-gamma +) were not inhibitory. Stat6ko Vgamma 4+ cells (IFN-gamma +) significantly enhanced myocarditis. Stat4ko Vgamma 4+ cells (IL-4+) neither inhibited nor enhanced disease. These results show that distinct gamma delta -T-cell subsets control myocarditis susceptibility and bias the CD4+-Th-cell response. The cytokines produced by the Vgamma subpopulation have a significant influence on the CD4+-Th-cell phenotype.

* Corresponding author. Mailing address: University of Vermont, Department of Pathology, 208 S. Park Dr., Suite 2, Colchester, VT 05446. Phone: (802) 656-8944. Fax: (802) 656-8965. E-mail: shuber{at}salus.med.uvm.edu.

Journal of Virology, July 2001, p. 5860-5869, Vol. 75, No. 13
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.13.5860-5869.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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