RESUMEN
The existence of gammadelta 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 gammadelta 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 beta TCR knockout (KO) mice. VV-infected mice deficient in gammadelta 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-gamma-producing gammadelta 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 gammadelta T cells in the spleen in uninfected beta TCR KO mice, as demonstrated by limiting dilution assay. Also, like NK cells, another mediator of innate immunity to viruses, gammadelta T cells in uninfected beta TCR KO mice expressed constitutive cytolytic activity. This cytotoxicity was enhanced and included a broader range of targets after VV infection. VV-infected beta TCR KO mice cleared most of the virus by day 8 PI, the peak of the gammadelta T cell response, but thereafter the gammadelta T cell number declined and the virus recrudesced. Thus, gammadelta 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.
Asunto(s)
Receptores de Antígenos de Linfocitos T gamma-delta/biosíntesis , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Virus Vaccinia/inmunología , Vaccinia/inmunología , Vaccinia/virología , Animales , Movimiento Celular/genética , Movimiento Celular/inmunología , Pruebas Inmunológicas de Citotoxicidad , Citotoxicidad Inmunológica/genética , Epítopos de Linfocito T/análisis , Genes Codificadores de la Cadena beta de los Receptores de Linfocito T , Predisposición Genética a la Enfermedad , Inmunidad Celular/genética , Inmunidad Innata/genética , Cinética , Activación de Linfocitos/genética , Recuento de Linfocitos , Depleción Linfocítica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Cavidad Peritoneal/citología , Receptores de Antígenos de Linfocitos T gamma-delta/deficiencia , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Tasa de Supervivencia , Subgrupos de Linfocitos T/virología , Linfocitos T Citotóxicos/inmunología , Vaccinia/genética , Vaccinia/mortalidad , Replicación Viral/genética , Replicación Viral/inmunologíaRESUMEN
Using a variety of techniques, including limiting dilution assays (LDA), intracellular IFNgamma assays, and Db-IgG1 MHC dimer staining to measure viral peptide-specific T cell number and function, we show here that heterologous virus infections quantitatively delete and qualitatively alter the memory pool of T cells specific to a previously encountered virus. We also show that a prior history of a virus infection can alter the hierarchy of the immunodominant peptide response to a second virus and that virus infections selectively reactivate memory T cells with distinct specificities to earlier viruses. These results are consistent with a model for the immune system that accommodates memory T cell populations for multiple pathogens over the course of a lifetime.