CHARACTERIZATION OF NATURAL PEPTIDE LIGANDS FOR HLA-B-ASTERISK-4402 AND HLA-B-ASTERISK-4403 - IMPLICATIONS FOR PEPTIDE INVOLVEMENT IN ALLORECOGNITION OF A SINGLE AMINO-ACID CHANGE IN THE HLA-B44 HEAVY-CHAIN

This study describes the characterization of endogenous peptides assoc iated with the two major subtypes of HLA-B44. The two subtypes differ for a single amino acid substitution from Asp (HLA-B4402) to Leu (HLA -B4403) in position 156 of the alpha 2 domain, causing strong allorea ctivity in vivo. In order to study the involvement of peptides in this phenomenon, the peptide motifs of the two subtypes were determined fr om natural peptide pools using Edman degradation. The motif was found to be essentially identical for HLA-B4402 and -B*4403, with a strong predominance for Glu at position 2, Tyr or Phe at positions 9 and 10 a nd hydrophobic residues, especially Met, at position 3. Two individual naturally processed ligands of HLA-B4403 were sequenced and shown to be derived from intracellularly expressed proteins found in protein s equence databases. The sequence of these natural peptide ligands confo rm well to the determined motif. These data will allow the prediction of HLA-B44 restricted peptide epitopes from viral and tumor antigens o f known amino acid sequences. Moreover, they indicate that the peptide repertoire presented by HLA-B4402 and -B*4403 is very similar, sugge sting that the strong alloresponse between these two subtypes is not d ue to presentation of a different set of self peptides.