Pathogen-Induced Proapoptotic Phenotype and High CD95 (Fas) Expression Accompany a Suboptimal CD8+ T-Cell Response: Reversal by Adenoviral Vaccine

MHC class Ia-restricted CD8+ T cells are important mediators of the adaptive immune response against infections caused by intracellular microorganisms. Whereas antigen-specific effector CD8+ T cells can clear infection caused by intracellular pathogens, in some circumstances, the immune response is suboptimal and the microorganisms survive, causing host death or chronic infection. Here, we explored the cellular and molecular mechanisms that could explain why CD8+ T cell-mediated immunity during infection with the human protozoan parasite Trypanosoma cruzi is not optimal. For that purpose, we compared the CD8+ T-cell mediated immune responses in mice infected with T. cruzi or vaccinated with a recombinant adenovirus expressing an immunodominant parasite antigen. Several functional and phenotypic characteristics of specific CD8+ T cells overlapped. Among few exceptions was an accelerated expansion of the immune response in adenoviral vaccinated mice when compared to infected ones. Also, there was an upregulated expression of the apoptotic-signaling receptor CD95 on the surface of specific T cells from infected mice, which was not observed in the case of adenoviral-vaccinated mice. Most importantly, adenoviral vaccine provided at the time of infection significantly reduced the upregulation of CD95 expression and the proapoptotic phenotype of pathogen-specific CD8+ cells expanded during infection. In parallel, infected adenovirus-vaccinated mice had a stronger CD8 T-cell mediated immune response and survived an otherwise lethal infection. We concluded that a suboptimal CD8+ T-cell response is associated with an upregulation of CD95 expression and a proapoptotic phenotype. Both can be blocked by adenoviral vaccination

Anti-tumor DNA vaccines based on the expression of human papillomavirus-16 E6/E7 oncoproteins genetically fused with the glycoprotein D from herpes simplex virus-1.

DNA vaccines encoding the human papillomavirus type-16 (HPV-16) E6 and E7 oncoproteins genetically fused to the human herpes simplex virus type 1 (HSV-1) gD protein were tested in mice for induction of T cell-mediated immunity and protection against tumor cell challenge. Hybrid genes, generated after insertion of E6 or E7-encoding sequences into internal sites of the gD-encoding gene, were transcribed in vitro and the chimeric proteins were expressed at the surface of in vitro-transfected mammalian cells. Female C57BL/6 mice immunized with 4 intramuscular doses (100 microg of DNA/dose) of the DNA vaccines encoding E7 efficiently generated E7-specific CD8(+) T cells. Vaccination of mice with the DNA vaccines encoding the E7, or both E6 and E7, conferred complete protection to challenges from TC-1 tumor cells and partial therapeutic effect (40%) in mice inoculated with TC-1 cells on the same day or 5 days prior to the first vaccine dose