Coxsackievirus B (CVB) infections cause considerable morbidity and mortality, and strategies to treat or prevent CVB-associated disease may benefit from a clearer understanding of the host immune response to virus infection. CVB3 induces minimal endogenous naïve CD8 and CD4 T cell responses, possibly because viral antigen (Ag) presentation is extremely limited. Several CVB3 proteins are known to cooperatively downregulate MHC class I on infected cells in vitro. In this study, we used transgenic (Tg) CD4 and CD8 T cells as sensors to evaluate viral Ag presentation by the MHC class I and class II pathways in vivo. Our analysis revealed a striking difference in Tg T cell responses: CD4 Tg T cells proliferated in CVB3-infected mice whereas CD8 Tg T cells failed to divide. Moreover, virus infection generated multi-functional memory CD4 T cells, which expanded dramatically following challenge infection, and rapidly differentiated into secondary effector Th1 cells. Although naïve CD8 Tg T cells were unresponsive to CVB3, they persisted in the host and responded vigorously when stimulated by a different virus encoding their cognate Ag. These data suggest that CVB3 utilizes a powerful immune evasion strategy in vivo that differentially affects the two Ag presentation pathways, and that this difference regulates the host's capacity to mount CD4 and CD8 T cell responses. This work was supported by NIH R01 AI42314 and T32 NS41219.