DNA sequence of HLA-A11: remarkable homology with HLA-A3 allows identification of residues involved in epitopes recognized by antibodies and T cells

Abstract

The human class I alleles HLA-A11 and HLA-A3 have a well-documented history of serological cross-reactivity. This cross-reactivity suggests that they are closely related, a suggestion which is supported by the fact that the HLA-A11 and HLA-A3 genes are distinguished from all other A-locus genes by a restriction fragment length polymorphism observed in Bam HI digests. To examine the extent of sequence homology between HLA-A11 and HLA-A3, we have cloned the HLA-A11 gene and sequenced the coding regions (exons). The results reveal that HLA-A11 and HLA-A3 display the highest degree of homology reported for any pair of serologically defined class I alleles. Only nine base differences resulting in six amino acid differences were observed in exons 2-8. One of the amino acid substitutions is in the alpha 1 domain and the other five are in the alpha 2 domain. comparison of this sequence with that of other human class I molecules implicates Gln62 as a critical residue involved in HLA-A11 - HLA-A3 serological cross-reactivity. In addition, the amino acid sequence allowed us to successfully predict cross-reactive recognition of HLA-A11 by cytotoxic T lymphocytes specific for a rare subtype of HLA-A3, HLA-A3.2. This result provides further support for the importance of the alpha 2 domain residues 152 and 156 in forming determinants on class I molecules that are recognized by cytotoxic T lymphocytes.