Herpes simplex virus type 1 (HSV-1) produces acute mucocutaneous infections, spread to sensory ganglia, and establishment of latency. In addition, neurovirulent strains have potential to invade the central nervous system (CNS), with potentially a lethal outcome. Early activation of defenses at all stages is essential to limit virus load and reduce the risk of neuronal damage, extensive zosteriform skin lesions, and catastrophic spread to the CNS. NKT cells respond rapidly, and we have shown previously that CD1d-deficient mice are compromised in controlling a neuroinvasive isolate of HSV-1. We now compare infection in J␣18 GKO and CD1d GKO mice, allowing direct assessment of the importance of invariant V␣14؉ NKT cells and deduction of the role of the CD1d-restricted NKT cells with diverse T-cell receptors. The results indicate that both subsets of NKT cells contribute to virus control both in the afferent phase of infection and in determining the mortality, neuroinvasion, loss of sensory neurons, size of zosteriform, lesions and levels of latency. In particular, both are crucial determinants of clinical outcome, providing protection equivalent to a 1-log dose of virus. These NKT cells can be expected to provide protection at doses of virus that might be encountered naturally.The murine zosteriform model of herpes simplex virus type 1 (HSV-1) infection mimics infections that occur in humans (31). During the afferent phase of the infection, the virus replicates in the skin and then enters sensory nerve endings to reach the dorsal root ganglia (DRG), where it undergoes further rounds of replication. This phase is followed by anterograde flow of infectious virus to the skin, giving rise to vesicular bandlike (zosteriform) lesions in the dermatomes supplied by the infected ganglia. In severe infections, the virus may also spread to adjacent DRG and to the central nervous system (CNS). Adaptive immunity is vital for limiting virus replication in the DRG, anterograde spread to the respective dermatomes, and extension to the CNS (for a review, see reference 21). HSV-1 spread to the DRG gives rise to life-long latent infection of sensory neurons, thought to be kept in check by adaptive immunity (for a review, see reference 20).The precise mechanisms that determine the outcome of HSV-1 infection are complex and incompletely understood (21, 28). Innate immune mechanisms, including interferons and NK cells, limit the local spread of the virus and its entry into sensory nerve endings at sites of infection (37). As adaptive immunity develops, T cells become dominant factors in determining outcome. Although the antiviral actions of CD4 ϩ T cells are confined mainly to the formation and severity of zosteriform lesions in the skin (24), virus-specific CD8 ϩ T cells are important in reducing the severity of zosteriform lesions (43), in protecting infected neurons in DRG from destruction, and in clearing infectious virus (32). These T cells are also thought to play a major part in the long-term containment of latent infection withi...