We have bred to homozygosity gene disruptions for the transporter associated with antigen processing 1 (TAP1) and beta 2-microglobulin (beta 2m), each of which plays a distinct role in providing class I MHC subunits. Surface expression of H-2Kb or Db on cells derived from TAP1/beta 2m -/- mice was undetectable by immunofluorescence or immunoprecipitation, unlike the situation observed for TAP1 -/- and beta 2m -/- single mutant mice. Yet, TAP1/beta 2m -/- cells were able to elicit a CD8+ cytotoxic T cell (CTL) response in mice of different H-2 haplotypes and could be killed by anti-H-2b specific CTL. Furthermore, TAP1/beta 2m -/- skin grafts were rejected by bm1 mutant mice. This suggests that very low levels of conformed class I heavy chains can reach the cell surface even in the complete absence of TAP1 and beta 2m gene products, and that these molecules may select a functional CD8+ T cell repertoire. Indeed, CD4-CD8+ T cells were detected in TAP1/beta 2m -/- mice, but in numbers lower than in either of the single mutant mice. Nonetheless, it was possible to elicit a CD8+ allospecific and H-2b reactive CTL response in TAP1/beta 2m -/- mice. In line with this, TAP1/beta 2m -/- mice rapidly rejected TAP1/beta 2m +/- skin grafts. Our results suggest that some MHC class I heavy chains in TAP1/beta 2m -/- cells can reach the cell surface in a form that allows recognition by allospecific CTL and positive selection of CD8+ T cells.