Novel role of CD8⁺ T cells and major histocompatibility complex class I genes in the generation of protective CD4⁺ Th1 0responses during retrovirus infection in mice

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-2^b allele at major histocompatibility complex (MHC) class II loci, a single H-2D^b MHC class I allele was sufficient for the development of a CD4⁺ Th1 response to FV. This effect of H-2D^b 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-2^a mice induced FV-specific responses of H-2D^d-restricted CD8⁺ cytotoxic T lymphocytes (CTL). Adoptive transfer of vaccine-primed CD8⁺ T cells to naive H-2^a 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.