Culturing naive T cells with 50 microM selected HIV-1 envelope peptides for 6 days in the presence of IL-2 drives the emergence of a substantial CD8(+) population that secretes IFN-gamma following short-term stimulation with 1 microM peptide. This response is H-2K(b) restricted, epitope specific, and requires the continuing presence of peptide. The same effect was found for known H-2D(b)-restricted peptides from two influenza virus proteins. The great majority of these influenza-specific CD8(+)IFN-gamma(+) T cells neither stained with the cognate tetramer nor expressed the TCR Vbeta bias that is characteristic of the CD8(+) set expanded in vivo during an infection. Thus, multipoint binding of low affinity TCRs on naive CD8(+) T cells can drive peptide-specific cytokine production. However, at least for two influenza-derived epitopes, the avidity of the TCR-MHC peptide interaction appears to be insufficient to stabilize a tetrameric complex of MHC class I glycoprotein plus peptide on the lymphocyte surface.