Naturally occurring TAP-dependent specific T-cell tolerance for a variant of an immunodominant retroviral cytotoxic T-lymphocyte epitope

Upon immunization and restimulation with tumors induced by the endogenous A KR/Gross murine leukemia virus (MuLV), C57BL/6 mice generate vigorous H-2K( b)-restricted cytotoxic T-lymphocyte (CTL) responses to a determinant (KSPW FTTL) derived from the p15E transmembrane portion of the viral envelope gly coprotein. By contrast, the highly homologous determinant RSPWFTTL, express ed by tumor cells induced by Friend/Moloney/Rauscher (FMR) MuLV, is not imm unogenic, even when presented to the immune system as vaccinia virus-encode d cytosolic or endoplasmic reticulum (ER)-targeted minigene products. Such minigene products are usually highly immunogenic since they bypass the need for cells to liberate the peptide or transport the peptide into the ER by the transporter associated with antigen processing (TAP). Using KSPWFTTL-sp ecific CTLs that cross-react with RSPWFTTL, we previously demonstrated that presentation of RSPWFTTL from its natural viral gene product is TAP depend ent. Here, we show first that C57BL/6 mice express mRNA encoding RSPWFTTL b ut not KSPWFTTL and second that the ER-targeted RSPWFTTL minigene product i s highly immunogenic in C57BL/6 mice with a targeted deletion in TAP1. Thes e findings provide the initial demonstration of TAP-dependent tolerance ind uction to a specific self peptide and demonstrate that this contributes to the differential recognition of RSPWFTTL and KSPWFTTL by C57BL/6 mice.