MECHANISMS OF PROTECTION AGAINST RETROVIRAL INFECTIONS INDUCED WITH A SINGLE-EPITOPE CD4^+ T-CELL VACCINE

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We have previously shown that immunization with a synthetic peptide that contains a single CD4^+ T-cell epitope protects highly susceptible mice against immunosuppressive Friend retrovirus infection. Cells producing infectious Friend virus were rapidly eliminated from the spleen of mice that had been immunized with the single- epitope peptide. However, actual effector mechanisms induced through T-helper cell responses after Friend virus inoculation were unknown. When cytotoxic effector cells detected in the early phase of Friend retrovirus infection were separated based on their expression of cell surface markers, those lacking CD4 and CD8 but expressing natural killer cell markers were found to constitute the majority of effector cells that lysed Friend virus-induced leukemia cells. Depletion of natural killer cells by injecting anti-asialo GM_1 antibody did not affect the number of CD4^+ or CD8^+ T cells in the spleen, virus antigen-specific proliferative responses of CD4^+ T cells, … More or cytotoxic activity against Friend virus-induced leukemia cells exerted by CD8^+ effector cells, but completely abolished the effect of peptide immunization. Although the above enhancement of natural killer cell activity in the early stage of Friend virus infection was also observed in mice given no peptide, these results have demonstrated the importance and requirement of natural killer cells in the vaccine-induced resistance against the retroviral infection.Other sets of cell-depletion and transfer experiments also showed that CD4^+ and CD8^+ T cells were required for the vaccine-induced protection against Friend retrovirus infection, and the presence of CD4^+ T cells was absolutely required for the production, but not just class switching, of virus-neutralizing antibodies. Thus, these results clearly show that a single-epitope CD4^+ T cell vaccine induces immune resistance against Friend retrovirus infection by rapidly activating multiple effector mechanism soon after the virus infection including CD4^+ and CD8^+ cytotoxic effector cells, virus-neutralizing antibodies, and NK cells. Less