Few peptides dominate cytotoxic T lymphocyte responses to single and multiple minor histocompatibility antigens.

Minor histocompatibility (H) antigens are T cell recognized self proteins which can cause graft versus host disease or organ transplant rejection. We have analysed the number of peptide epitopes involved in cytotoxic T lymphocyte (CTL) responses to single or multiple minor H antigens. Bulk CTL responses were generated in H-2b mice differing in one (H-1), two (H-1 and H-25), or multiple (> 29) minor H loci, and HPLC separation was used to analyse the complexity of CTL recognized peptides. Anti-H-1 CTL recognize one out of 50 HPLC peptide fractions and recognition is H-2Kb restricted. The same peptide fraction is also recognized by anti-H-1/H-25 CTL and no additional epitopes are detected, indicating that the H-25 locus does not stimulate CTL when combined with H-1. CTL generated to multiple minor H loci (including H-1 and H-25) recognize two HPLC peptide fractions which are presented by H-2Db and H-2Kb class I molecules, respectively. The H-2Kb presented fraction is the same as that recognized by anti-H-1 and anti-H-1/H-25 CTL, and it is shown to contain a H-1-derived peptide. Subfractionation of the CTL recognized HPLC fractions is consistent with the presence of only one peptide epitope. Thus, in the responses analysed here one minor H locus encodes probably only one CTL epitope. The study provides a molecular explanation for immunodominance among minor H antigens, suggesting that dominant loci encode single peptide epitopes which are presented efficiently by MHC class I molecules enabling them to readily stimulate CTL responses.