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A Comparative Study of HLA Binding Affinity and Ligand Diversity: Implications for Generating Immunodominant CD8⁺ T Cell Responses¹

Xiangyu Rao^*, Ana Isabel C. A. Fontaine Costa, Debbie van Baarle and Can Kemir^2,*,

^* Department of Theoretical Biology/Bioinformatics, Utrecht University, Utrecht, The Netherlands; Department of Immunology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands; and Academic Biomedical Centre, Utrecht University, Utrecht, The Netherlands

Conventional CD8⁺ T cell responses against intracellular infectious agents are initiated upon recognition of pathogen-derived peptides presented at the cell surface of infected cells in the context of MHC class I molecules. Among the major MHC class I loci, HLA-B is the swiftest evolving and the most polymorphic locus. Additionally, responses restricted by HLA-B molecules tend to be dominant, and most associations with susceptibility or protection against infectious diseases have been assigned to HLA-B alleles. To assess whether the differences in responses mediated via two major HLA class I loci, HLA-B and HLA-A, may already begin at the Ag presentation level, we have analyzed the diversity and binding affinity of their peptide repertoire by making use of curated pathogen-derived epitope data retrieved from the Immune Epitope Database and Analysis Resource, as well as in silico predicted epitopes. In contrast to our expectations, HLA-B alleles were found to have a less diverse peptide repertoire, which points toward a more restricted binding motif, and the respective average peptide binding affinity was shown to be lower than that of HLA-A-restricted epitopes. This unexpected observation gives rise to new hypotheses concerning the mechanisms underlying immunodominance of CD8⁺ T cell responses.

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 by a HIPO (High Potential) grant from Universiteit Utrecht.

² Address correspondence and reprint requests to Dr. Can Kesmir, Department of Theoretical Biology/Bioinformatics, Padualaan 8, 3584 CH Utrecht, The Netherlands. E-mail address: C.Kesmir{at}uu.nl

³ Abbreviations used in this paper: IEDB, Immune Epitope Database and Analysis Resource; SMM, stabilized matrix method.

⁴ The online version of this article contains supplemental material.