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The nature of peptides presented by an HLA class I low expression allele

Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany

Correspondence: Britta Eiz-Vesper, Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. Phone: international +49.511532 9715. Fax: international +49.511.5329701. E-mail: eiz-vesper.britta{at}mh-hannover.de

ABSTRACT

Background: The functional integrity of human leukocyte antigen (HLA) low expression variants is a prerequisite for considering them as essential in the matching process of hematopoietic stem cell donors and recipients to diminish the risk of serious complications such as graft-versus-host disease or graft rejection. The HLA-A*3014L variant is missing a disulfide bridge in the 2 domain which could affect peptide binding and presentation to T cells.

Design and Methods: HLA-A*3014L and HLA-A*3001 were expressed as truncated variants and peptides were eluted and subjected to pool sequencing by Edman degradation as well as to single-peptide sequencing by mass spectrometry. Quantitative analysis of binding of in vivo presented peptides was performed by a flow cytometric peptide-binding assay using HLA-A*3001 and HLA-A*3014L-expressing B–LCLs.

Results: The truncated HLA-A*3014L protein was secreted in the supernatant and it was possible to elute and sequence peptides. Sequence analysis of these eluted peptides revealed no relevant differences to the peptide motif of HLA-A*3001, indicating that the Cys164Ser substitution does not substantially alter the spectrum of presented peptides. Strong binding of one of the shared in vivo identified HLA-A*3001/3014L ligands was confirmed in the peptide-binding assay.

Conclusions: This study is the first to demonstrate that HLA low expression variants are able to present peptides and, thus, can be considered as functionally active. When comparing peptide motifs, it is likely that HLA-A*3014L and HLA-A*3001 represent a permissive mismatch with low allogenicity in HSCT. These results indicate that surface expression as well as peptide-binding data of HLA variants with similar disulfide bridge variations (e.g. HLA-A*3211Q) need to be considered as functionally active in an allogeneic HSCT setting as long as the opposite has not been shown. Otherwise a relevant but not considered HLA mismatch could result in a severe allogeneic T-cell response and GvHD.

Key words: HLA-A*3014L, peptide motif, HLA low expression alleles, stem cell transplantation.