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

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 Vγ4 Vδ4 cells, which are strongly positive for gamma interferon (IFN-γ), whereas Vγ1 Vδ4 cells are increased in both H3 and H310A1 virus-infected animals. Depletion of Vγ1(+) cells using monoclonal anti-Vγ1 antibody enhanced myocarditis and CD4(+)-, IFN-γ(+)-cell responses in both H3- and H310A1-infected mice yet decreased the CD4(+)-, IL-4(+)-cell response. Depleting Vγ4(+) cells suppressed myocarditis and reduced CD4(+) IFN-γ(+) cells but increased CD4(+) IL-4(+) T cells. The role of cytokine production by Vγ1(+) and Vγ4(+) T cells was investigated by adoptively transferring these cells isolated from H3-infected BALB/c Stat4 knockout (Stat4ko) (defective in IFN-γ expression) or BALB/c Stat6ko (defective in IL-4 expression) mice into H3 virus-infected wild-type BALB/c recipients. Vγ4 and Vγ1(+) T cells from Stat4ko mice expressed IL-4 but no or minimal IFN-γ, whereas these cell populations derived from Stat6ko mice expressed IFN-γ but no IL-4. Stat4ko Vγ1(+) cells (IL-4(+)) suppress myocarditis. Stat6ko Vγ1(+) cells (IFN-γ(+)) were not inhibitory. Stat6ko Vγ4(+) cells (IFN-γ(+)) significantly enhanced myocarditis. Stat4ko Vγ4(+) cells (IL-4(+)) neither inhibited nor enhanced disease. These results show that distinct γδ-T-cell subsets control myocarditis susceptibility and bias the CD4(+)-Th-cell response. The cytokines produced by the Vγ subpopulation have a significant influence on the CD4(+)-Th-cell phenotype.