Protective Immunity to Genital Herpes Simpex Virus Type 2 Infection Is Mediated by T-bet

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Abstract
We show, for the first time, that the transcription factor T-bet, which is implicated in IFN-γ production, is required for the induction of vaccine-induced antiviral immune protection. T-bet was found to be important in both the innate and acquired immune protection against genital HSV-2 infection. T-bet−/− and T-bet+/+ mice were infected vaginally with HSV-2 and examined daily for disease and mortality. T-bet−/− mice had significantly higher virus titers than T-bet+/+ mice following a primary HSV-2 infection, and succumbed significantly earlier to the infection. This result was associated with an impaired NK cell cytotoxic capacity and NK cell-mediated IFN-γ production in the T-bet−/− mice. To assess the induction of acquired antiviral immune protection, mice were vaccinated with an attenuated virus before infection. Vaccinated T-bet−/− mice could not control viral replication following an HSV-2 challenge and had significantly higher virus titers and mortality rates than vaccinated T-bet+/+ mice that remained healthy. The impaired acquired immune protection in T-bet−/− mice was associated with a significantly decreased HSV-2-specific delayed-type hypersensitivity response and a significantly reduced HSV-2-specific IFN-γ production from CD4+ T cells. However, T-bet deficiency did not impair either the IFN-γ production or the cytotoxic capacity of HSV-2-specific CD8+ T cells. We conclude that T-bet plays a crucial role in both the innate defense and the generation of vaccine-induced immunity against genital HSV-2 infection in mice.