OVERLAP IN THE REPERTOIRES OF PEPTIDES BOUND IN-VIVO BY A GROUP OF RELATED CLASS-I HLA-B ALLOTYPES

Background: Polymorphism among class I molecules of the major histocom patibility complex (MHC) confers allotypic specificity on the peptides that these molecules bind and present to cytotoxic T lymphocytes. Evo lution of new human HLA class I alleles usually involves gene recombin ation events that replace a segment of one allele with the homologous region of another. In this study, the impact of these evolutionary cha nges has been assessed by comparison of the peptide-binding specificit ies of six related HLA-B allotypes. Results: Endogenous peptides bound by HLA-B star 5401, HLA-B star 5501, HLA-B star 5502, HLA-B star 5601 , HLA-B star 6701 and HLA-B star 0702 were characterized. Despite diff ering by 1-9 of the amino-acid residues comprising their peptide-bindi ng sites, all these allotypes share a dominant preference for peptides that have proline at position 2. Polymorphism results in differing se lection of carboxy-terminal and secondary anchor residues, but the pep tide-binding specificities are sufficiently similar that there is over lap in the repertoires of peptides bound by these allotypes. Complete sequence determination of individual peptides revealed four that could be isolated from two or more allotypes. Members of the closely relate d HLA-B22 family - HLA-B star 5401, HLA-B star 5501, HLA-B star 5502 a nd HLA-B star 5601 - show only minor differences in their peptide-bind ing specificities. This marked similarity is reflected at the function al level, as alloreactive cytotoxic T lymphocytes generated against HL A-B star 5401 and HLA-B star 5501 exhibited crossreactive recognition. Conclusion: The isolation of identical endogenously bound peptides fr om six HLA-B allotypes demonstrates overlap in the repertoires of pept ides bound in vivo by different allotypes. We speculate that the share d preference for binding peptides with proline at position 2 reflects a selective pressure to retain this specificity, which may be based up on peptide availability in vivo. Characterization of the overlap betwe en the repertoires of peptides bound by HLA-B allotypes could simplify the development of peptide-based vaccines that are targeted to cytoto xic T cells, as single peptides would be effective for humans of diffe rent HLA types.