Cytokine production by V gamma(+)-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 M310A1) differ by a single am ino acid mutation in the VP2 capsid protein. H3 induces severe myocarditis in BALB/c mice, but H310A1 is amyocarditic. Infection with H3, but not H310 A1, preferentially activates V gamma4 V delta4 cells, which are strongly po sitive for gamma interferon (IFN-gamma), whereas V gamma1 V delta4 cells ar e increased in both M3 and H310A1 virus-infected animals. Depletion of V ga mma1(+) cells using monoclonal anti-V gamma1 antibody enhanced myocarditis and CD4(+)-, IFN-gamma (+)-cell responses in IL-4(+)-cell response, Depleti ng V gamma4(+) cells both H3- and H310A1-infected mice yet decreased the CD 4(+), suppressed myocarditis and reduced CD4(+) IFN-gamma (+) cells but Inc reased CD4(+) IL-4(+) T cells. The role of cytokine production by V gamma1( +) and V gamma4(+) T cells was investigated by adoptively transferring thes e cells isolated from MS-infected BALB/c Stat4 knockout (Stat4ko) (defectiv e in IFN-gamma expression) or BALB/c Stat6ko (defective in IL-4 expression) mice into H3 virus-infected wild-type BALB/c recipients. V gamma4 and V ga mma1+ T cells from Stat4ko mice expressed IL-4 but no or minimal IFN-gamma, whereas these cell populations derived from Stat6ko mice expressed IFN-gam ma but no IL-4, Stat4ko V gamma1(+) cells (IL-4(+)) suppress myocarditis, S tat6ko V gamma1(+) cells (IFN-gamma (+)) were not inhibitory, Stat6ko V gam ma4(+) cells (IFN-gamma (+)) significantly enhanced myocarditis. Stat lko V gamma4(+) cells (IL-4(+)) neither inhibited nor enhanced disease. These re sults show that distinct gamma delta -T-cell subsets control myocarditis su sceptibility and bias the CD4(+)-Th-cell response. The cytokines produced b y the V gamma subpopulation have a significant influence on the CD4(+)-Th-c ell phenotype,