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Steric Hindrance and Fast Dissociation Explain the Lack of Immunogenicity of the Minor Histocompatibility HA-1^Arg Null Allele ¹

Eric Spierings^2,*, Stéphanie Gras^2,3,, Jean-Baptiste Reiser^2,, Bregje Mommaas^*, Mathilde Almekinders^*, Michel G. D. Kester, Anne Chouquet, Madalen Le Gorrec, Jan W. Drijfhout^*, Ferry Ossendorp^*, Dominique Housset^4, and Els Goulmy^4,*

^* Department of Immunohematology and Blood Transfusion, Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands; and Institut de Biologie Structurale Jean-Pierre Ebel, Unité Mixte de Recherche 5075 (CEA, CNRS, UJF, PSB), Grenoble, France

The di-allelic HLA-A2 restricted minor histocompatibility Ag HA-1 locus codes for the highly immunogenic HA-1^His and the nonimmunogenic HA-1^Arg 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-1^Arg 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-1^Arg peptide immunogenicity essential for the choice of tumor peptides for stem cell-based immunotherapeutic application.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants of the Netherlands Organization for Scientific Research, the 6th Framework Programme "Allostem" of the European Commission, and by Grant ANR-05-MIIM-019 from the Agence Nationale de la Recherche.

² E.S., S.G., and J.-B.R. contributed equally to this work.

³ Current address: The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.

⁴ Address correspondence and reprint requests to Dr. Els Goulmy, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, PO Box 9600, 2300RC Leiden, The Netherlands, E-mail address: e.a.j.m.goulmy{at}lumc.nl or to Dr. Dominique Housset, Institut de Biologie Structurale Jean-Pierre Ebel, Unité Mixte de Recherche 5075 (CEA, CNRS, UJF, PSB), 41 rue Jules Horowitz, F-38027 Grenoble, France, E-mail address: dominique.housset{at}ibs.fr

⁵ Abbreviations used in this paper: SCT, stem cell transplantation; ER, endoplasmic reticulum.

⁶ The online version of this article contains supplemental material.