Differential binding of a minor histocompatibility antigen peptide to H-2 class I molecules correlates with immune responsiveness.
Minor histocompatibility (H) Ag are recognized in the context of MHC class I (K/D) molecules and can constitute a strong barrier to tissue transplantation. The products encoded by the MHC (H-2 in mice) have been shown recently to be Ag-presenting molecules that bind foreign and self peptides in their peptide binding sites. Different class I molecules preferentially bind different arrays of endogenous peptides for presentation to CTL. Previous studies showed that the Kb-restricted CTL response to one minor histocompatibility Ag, H-4, varied in different Kb mutants. One possible basis for this variation might be that the response is regulated by the level of binding of an H-4 peptide by class I molecules. To analyze this possibility, we initiated studies to identify the H-4 peptide that is included in the array of self peptides. The complete mixture of peptides eluted from Kb molecules of H-4+ tumor cells was able to sensitize H-4- targets for lysis by H-4-specific CTL. The presence of a specific H-4 peptide was confirmed when the radiolabeled peptide mix eluted from Kb molecules was separated by HPLC. Only one peak in the profile of H-4+ tumor peptides was capable of sensitizing H-4- targets for lysis by H-4-specific CTL; this active peak was absent in H-4 mutant cells. Peptide mixtures eluted from a panel of Kb mutant molecules extracted from H-4+ lymphocytes varied in their capacities to sensitize targets for H-4-specific lysis and the relative sensitization correlated with the demonstrated capacity of mutant mice to generate H-4-specific CTL. Therefore, the highly specific genetic control of the T cell response to the H-4 minor histocompatibility Ag appears to be due to the differential binding of an H-4 peptide by class I molecules.
Wettstein
P J
PJ
Department of Surgery, Mayo Foundation, Rochester, MN 55905.
van Bleek
G M
GM
Nathenson
S G
SG
D000818:Animals; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003602:Cytotoxicity, Immunologic; D000939:Epitopes; D006183:H-2 Antigens / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000939:Epitopes; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015778:Minor Histocompatibility Antigens; D010446:Peptide Fragments