A subset of CD161 (NK1) T cells express an invariant Vα14Jα281TCR-α chain (Vαinvt T cells) and produce Th2 and Th1cytokines rapidly in response to CD1d, but their physiological function(s) remain unclear. We have found that CD1d-reactive T cells mediate to resistance against the acute, cytopathic virus diabetogenic encephalomyocarditis virus (EMCV-D) in relatively Th1-biased,C57BL/6-based backgrounds. We show now that these results generalize toTh2-biased, hypersensitive BALB/c mice. CD1d-KO BALB/c mice were more susceptible to EMCV-D. Furthermore, α-galactosylceramide(α-GalCer), a CD1d-presented lipid antigen that specifically activates Vαinvt T cells, protected wild-type (WT) mice against EMCV-D-induced encephalitis, myocarditis, and diabetes. In contrast, neither CD1d-KO nor Jα281-KO mice were protected byα-GalCer. Finally, disease in Jα281-KO mice was comparable to WT,indicating for the first time equivalent roles for CD1d-reactiveVαinvt and noninvariant T cells in resistance to acute viral infection. A model for how CD1d-reactive T cells can initiate immune responses, which synthesizes current results, is presented.