Innate Immunity to Viruses: Control of Vaccinia Virus Infection by γδ T Cells

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Abstract
The existence of γδ T cells has been known for over 15 years, but their significance in innate immunity to virus infections has not been determined. We show here that γδ T cells are well suited to provide a rapid response to virus infection and demonstrate their role in innate resistance to vaccinia virus (VV) infection in both normal C57BL/6 and β TCR knockout (KO) mice. VV-infected mice deficient in γδ T cells had significantly higher VV titers early postinfection (PI) and increased mortality when compared with control mice. There was a rapid and profound VV-induced increase in IFN-γ-producing γδ T cells in the peritoneal cavity and spleen of VV-infected mice beginning as early as day 2 PI. This rapid response occurred in the absence of priming, as there was constitutively a significant frequency of VV-specific γδ T cells in the spleen in uninfected β TCR KO mice, as demonstrated by limiting dilution assay. Also, like NK cells, another mediator of innate immunity to viruses, γδ T cells in uninfected β TCR KO mice expressed constitutive cytolytic activity. This cytotoxicity was enhanced and included a broader range of targets after VV infection. VV-infected β TCR KO mice cleared most of the virus by day 8 PI, the peak of the γδ T cell response, but thereafter the γδ T cell number declined and the virus recrudesced. Thus, γδ T cells can be mediators of innate immunity to viruses, having a significant impact on virus replication early in infection in the presence or absence of the adaptive immune response.