FEW PEPTIDES DOMINATE CYTOTOXIC T-LYMPHOCYTE RESPONSES TO SINGLE AND MULTIPLE MINOR HISTOCOMPATIBILITY ANTIGENS

Minor histocompatibility (H) antigens are T cell recognized self prote ins which can cause graft versus host disease or organ transplant reje ction. We have analysed the number of peptide epitopes involved in cyt otoxic T lymphocyte (CTL) responses to single or multiple minor H anti gens. 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 se paration was used to analyse the complexity of CTL recognized peptides . Anti-H-1 CTL recognize one out of 50 HPLC peptide fractions and reco gnition is H-2K(b) restricted. The same peptide fraction is also recog nized by anti-H-1/H-25 CTL and no additional epitopes are detected, in dicating 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-2D(b) an d H-2K(b) class I molecules, respectively. The H-2K(b) presented fract ion 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 o nly one peptide epitope. Thus, in the responses analysed here one mino r H locus encodes probably only one CTL epitope. The study provides a molecular explanation for immunodominance among minor H antigens, sugg esting that dominant loci encode single peptide epitopes which are pre sented efficiently by MHC class I molecules enabling them to readily s timulate CTL responses.