TAP-independent induction of N-myristoylated lipopeptide-specific CTLs in transgenic mice expressing the rhesus MHC class I allomorph, Mamu-B*098

A novel subset of classical major histocompatibility complex class I molecules has recently been identified in rhesus monkeys that mediates the presentation of N-myristoylated lipopeptides, rather than conventional peptides, to CD8+ cytotoxic T lymphocytes (CTLs). For example, the rhesus Mamu-B*098 allomorph binds an N-terminal 5-mer fragment (C14 fatty acid-Gly-Gly-Ala-Ile-Ser; C14nef5) derived from the N-myristoylated SIV Nef protein and activates C14nef5-specific CTLs. Additionally, a transporter for antigen presentation (TAP)-independent cell-surface expression was observed for Mamu-B*098 in the in vitro transfection experiments, leading us to hypothesize that TAP-independent pathways may exist for CTL activation. To address this directly, we generated transgenic mice expressing Mamu-B*098 and analyzed its function under TAP-deficient conditions. We first confirmed that its expression level was unchanged on the surface of TAP-deficient cells compared with that of TAP-sufficient cells. Second, the CD8+ T cell population, but not the CD4+ T cell population, increased in TAP knockout (KO) mice as a result of the acquisition of Mamu-B*098 expression. Third, C14nef5-specific, Mamu-B*098-restricted CD8+ T cells were readily inducible in Mamu-B*098 transgenic/TAP KO but not in nontransgenic/TAP KO mice. Finally, the CD8+ T cells expressed cytolytic granule contents and functioned as CTLs. These findings provide evidence that in addition to conventional peptide-specific CTL responses that require TAP, an alternative TAP-independent pathway for CTL activation exists in primates. This novel pathway may be valuable when TAP is targeted by pathogenic viruses for immune evasion. We propose that the established concept of major histocompatibility complex class I biology may require modifications to incorporate TAP-independent pathways of lipopeptide-specific CTL responses.