The immunogenicity of a new human minor histocompatibility antigen resultsfrom differential antigen processing

Minor histocompatibility antigens (mHAgs) present a significant impediment to organ and bone marrow transplantation between KLA-identical donor and re cipient pairs. Here we report the identification of a new HLA-A*0201-restri cted mHAg, HA-8. Designation of this mHAg as HA-8 is based on the nomenclat ure of Goulmy (Goulmy, E. 1996. Curr. Opin. Immunol. 8:75-81). This peptide , RTLDKVLEV, is derived from KIAA0020, a gene of unknown function located o n chromosome 9. Polymorphic alleles of KIAA0020 encode the alternative sequ ences PTLDKVLEV and PTLDKVLEL. Genotypic analysis demonstrated that the HA- 8-specific cytotoxic T lymphocyte (CTL) clone SKH-13 recognized only cells that expressed the allele encoding R at P1. However, when PTLDKVLEV was pul sed onto cells, or when a minigene encoding this sequence was used to artif icially translocate this peptide into the endoplasmic reticulum, it was rec ognized by CTLs nearly as well as RTLDKVLEV. This indicates that the failur e of CTLs to recognize cells expressing the PTLDKVLEV-encoding allele of KI AA0020 is due to a failure of this peptide to be appropriately proteolyzed or transported. Consistent with the latter possibility, PTLDKVLEV and its l onger precursors were transported poorly compared with RTLDKVLEV by transpo rter associated with antigen processing (TAP). These studies identify a new human mHAg and provide the first evidence that minor histocompatibility di fferences can result from the altered processing of potential antigens rath er than differences in interaction with the relevant major histocompatibili ty complex molecule or T cell receptor.