A Shift in the Requirement for CD4+T Cells in the Generation of AKR/Gross MuLV-Specific CTL in AKR.H-2b:Fv-1bMice Occurs Prior to the Onset of Age-Dependent CTL Nonresponsiveness

In the current study, the elimination of CD4+T cells from B6 mice, by treatment with anti-CD4 monoclonal antibody, had little effect on their ability to mount an AKR/Gross (MuLV)-specific CTL response. In contrast, for AKR.H-2b:Fv-1bmice, there was a shift as the mice aged from 5 to 7 weeks to a requirement for CD4+T cells for AKR/Gross MuLV-specific CTL generation. When CD4+T-cell-depleted AKR.H-2b:Fv-1bresponder mice were immunized at 5 weeks of age they were able to elicit a strong anti-AKR/Gross MuLV CTL response. However, if the CD4+T-cell depletion was done at 6 weeks and then the mice were primedin vivo,their antiviral CTL responsiveness was markedly decreased. Following CD4+T-cell depletion at 7 weeks the mice were totally incapable of generating anti-AKR/Gross MuLV-specific CTL. AKR/Gross MuLV-specific CTL isolated from AKR.H-2b:Fv-1bmice recognized the class I-restricted immunodominant epitope (KSPWFTTL) and three subdominant epitopes, previously identified as CTL epitopes for B6 mice. Analysis of IL-2, IFN-γ, IL-4, and IL-10 lymphokine profiles in supernates harvested from MLTC wells, and the results of supernate transfer experiments, suggested that the age-dependent shift to CD4+T-cell dependence in AKR.H-2b:Fv-1bmice does not correlate with an obvious change in thein vitrolymphokine profiles. Experiments in which exogenous IL-2 was used to supplementin vitrocultures containing CD4+T-cell-depleted 7-week responder mice suggested that the CD4+T-cell requirement was at thein vivopriming stage of antiviral CTL generation. These data suggested a fundamental change in virus-specific CTL which correlates with slight aging in the AKR.H-2b:Fv-1bmouse strain. To our knowledge, this is the first report of a shift in the requirement for CD4+T lymphocytes for the generation of virus-specific CTL over such a short period of time. Moreover, it is of interest that this shift in CD4+T-cell-dependence by antiviral CTL occurs just prior to the onset of CTL nonresponsiveness in the AKR.H-2b:Fv-1bmouse strain.