CD4+ Thl responses to virus infections are often necessary for the development and maintenance of virus-specific CD8+ T-cell responses. However, in the present study with Friend murine retrovirus (FV), the reverse was also found to be true. In the absence of a responder H-2b allele at major histocompatibility complex (MHC) class II loci, a single H-2Db MHC class I allele was sufficient for the development of a CD4+ Th1 response to FV. This effect of H-2Db on CD4+ T-cell responses was dependent on CD8+ T cells, as demonstrated by depletion studies. A direct effect of CD8+ T-cell help in the development of CD4+ Thl responses to FV was also shown in vaccine studies. Vaccination of nonresponder H-2a mice induced FV-specific responses of H-2Dd-restricted CD8+ cytotoxic T lymphocytes (CTL). Adoptive transfer of vaccine-primed CD8+ T cells to naive H-2a mice prior to infection resulted in the generation of FV specific CD4+ Thl responses. This novel helper effect of CD8+ T cells could be an important mechanism in the development of CD4+ Thl responses following vaccinations that induce CD8+ CTL responses. The ability of MHC class I genes to facilitate CD4+ Thl development could also be considerable evolutionary advantage by allowing a wider variety of MHC genotypes to generate protective immune responses against intracellular pathogens.