In experiments to study the impact of deficiency in CD4⁺ T cell help on the magnitude of CD8⁺ cytotoxic T cell response to pathogens, it was noted that in CD4 gene knockout mice, the CD8 population made significant responses to several nominally major histocompatibility complex (MHC) class II–restricted epitopes in addition to the expected responses to MHC class I–restricted epitopes. A similar response by CD8⁺ T cells to class II–restricted epitopes was not observed in wild-type mice, or in mice that had been acutely depleted of CD4⁺ T cells just before the immunization. Coincident with this unexpected response to class II–restricted epitopes, it was also observed that the CD8⁺ response to the class I–restricted epitopes was consistently lower in CD4^−/− mice than in wild-type mice. Further experiments suggested that these two observations are linked and that the CD8 population in CD4^−/− mice may contain a majority of T cells that were actually selected by recognition of MHC class II molecules in the thymus. These results have implications for understanding CD4 versus CD8 lineage commitment in the thymus, and for the practical use of CD4^−/− mice as models of helper deficiency.