Coxsackievirus B3 infections of C57BL/6 mice, which express the MHC class II IA but not IE Ag, results in virus replication in the heart but minimal myocarditis. In contrast, B1.Tg.E alpha mice, which are C57BL/6 mice transgenically induced to express IE Ag, develop significant myocarditis upon Coxsackievirus B3 infection. Despite this difference in inflammatory damage, cardiac virus titers are similar between C57BL16 and B1.Tg.E alpha mice. Removing gamma delta T cells from either strain by genetic manipulation (gamma delta knockout(ko)) changes the disease phenotype, C57BL/6 gamma delta ko mice show increased myocarditis, In contrast, B1.Tg.E alpha gamma delta ko mice show decreased cardiac inflammation. Flow cytometry revealed a difference in the gamma delta cell subsets in the two strains, with V gamma 1 dominating in C57BL16 mice, and V gamma 4 predominating B1.Tg.E alpha mice. This suggests that these two V gamma-defined subsets might have different functions. To test this possibility, we used mAb injection to deplete each subset. Mice depleted of V gamma 1 cells showed enhanced myocarditis, whereas those depleted of V gamma 4 cells suppressed myocarditis, Adoptively transfusing enriched V gamma 4(+) cells to the C57BL/6 and B1.Tg.E alpha gamma delta ko strains confirmed that the V gamma 4 subset promoted myocarditis, Th subset analysis suggests that V gamma 1(+) cells biased the CD4(+) T cells to a dominant Th2 cell response, whereas V gamma 4(+) cells biased CD4(+) T cells toward a dominant Th1 cell response.