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A Naturally Selected Dimorphism within the HLA-B44 Supertype Alters Class I Structure, Peptide Repertoire, and T Cell Recognition

Whitney A. Macdonald¹, Anthony W. Purcell¹, Nicole A. Mifsud¹, Lauren K. Ely², David S. Williams¹, Linus Chang¹, Jeffrey J. Gorman³, Craig S. Clements², Lars Kjer-Nielsen¹, David M. Koelle⁴, Scott R. Burrows⁵, Brian D. Tait⁶, Rhonda Holdsworth⁶, Andrew G. Brooks¹, George O. Lovrecz³, Louis Lu³, Jamie Rossjohn² and James McCluskey¹

¹ Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia
² The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3168, Australia
³ Commonwealth Scientific and Industrial Research Organization, Division of Health, Science and Nutrition, Parkville, Victoria 3052, Australia
⁴ Department of Medicine, University of Washington, Seattle, WA 98195
⁵ Queensland Institute of Medical Research, The Bancroft Centre, Herston 4029 Queensland, Australia
⁶ Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, South Melbourne,Victoria 3205, Australia

Address correspondence to James McCluskey, Dept. of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria 3010, Australia. Phone: 613-8344-5709; Fax: 613-9347-3226; email: jamesm1{at}unimelb.edu.au; or Jamie Rossjohn, The Protein Crystallography Unit, Dept. of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3168, Australia. Phone: 613-9905-3736; Fax: 613-9905-4699; email: Jamie.Rossjohn{at}med.monash.edu.au

HLA-B*4402 and B*4403 are naturally occurring MHC class I alleles that are both found at a high frequency in all human populations, and yet they only differ by one residue on the 2 helix (B*4402 Asp156B*4403 Leu156). CTLs discriminate between HLA-B*4402 and B*4403, and these allotypes stimulate strong mutual allogeneic responses reflecting their known barrier to hemopoeitic stem cell transplantation. Although HLA-B*4402 and B*4403 share >95% of their peptide repertoire, B*4403 presents more unique peptides than B*4402, consistent with the stronger T cell alloreactivity observed toward B*4403 compared with B*4402. Crystal structures of B*4402 and B*4403 show how the polymorphism at position 156 is completely buried and yet alters both the peptide and the heavy chain conformation, relaxing ligand selection by B*4403 compared with B*4402. Thus, the polymorphism between HLA-B*4402 and B*4403 modifies both peptide repertoire and T cell recognition, and is reflected in the paradoxically powerful alloreactivity that occurs across this "minimal" mismatch. The findings suggest that these closely related class I genes are maintained in diverse human populations through their differential impact on the selection of peptide ligands and the T cell repertoire.

Key Words: class I histocompatibility molecules • antigen presentation • crystallography • X-ray diffraction • graft rejection • polymorphism

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