Steric hindrance and fast dissociation explain the lack of immunogenicity of the minor histocompatibility HA-1Arg null allele

The di-allelic HLA-A2 restricted minor histocompatibility Ag HA-1 locus codes for the highly immunogenic HA-1His and the nonimmunogenic HA-1Arg nonapeptides, differing in one amino acid. The HA-1 His peptide is currently used for boosting the graft-vs-tumor responses after HLA matched HA-1 mismatched stem cell transplantation; usage of the HA-1Arg peptide would significantly enlarge the applicability for this therapy. Our studies on mechanisms causing the HA-1 unidirectional immunogenicity revealed marginal differences in proteasomal digestion, TAP translocation, and binding affinity, whereas both dissociation rates and structural analyses clearly showed marked differences in the stability of these two HLA-A2 bound alleles. These data provide a rationale for the lack of HA-1Arg peptide immunogenicity essential for the choice of tumor peptides for stem cell-based immunotherapeutic application.