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¹ The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia
² Cellular Immunology Laboratory, Queensland Institute of Medical Research, Brisbane 4029, Australia
³ Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute and ⁴ Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia

CORRESPONDENCE Jamie Rossjohn: jamie.rossjohn{at}med.monash.edu.au OR Scott R. Burrows: Scott.Burrows{at}qimr.edu.au

Human leukocyte antigen (HLA) gene polymorphism plays a critical role in protective immunity, disease susceptibility, autoimmunity, and drug hypersensitivity, yet the basis of how HLA polymorphism influences T cell receptor (TCR) recognition is unclear. We examined how a natural micropolymorphism in HLA-B44, an important and large HLA allelic family, affected antigen recognition. T cell–mediated immunity to an Epstein-Barr virus determinant (EENLLDFVRF) is enhanced when HLA-B*4405 was the presenting allotype compared with HLA-B*4402 or HLA-B*4403, each of which differ by just one amino acid. The micropolymorphism in these HLA-B44 allotypes altered the mode of binding and dynamics of the bound viral epitope. The structure of the TCR–HLA-B*4405^EENLLDFVRF complex revealed that peptide flexibility was a critical parameter in enabling preferential engagement with HLA-B*4405 in comparison to HLA-B*4402/03. Accordingly, major histocompatibility complex (MHC) polymorphism can alter the dynamics of the peptide-MHC landscape, resulting in fine-tuning of T cell responses between closely related allotypes.

Abbreviations used: β₂m, β₂-microglobulin; BSA, buried surface area; CDR, complementarity determining region; MHC-I, MHC class I; pMHC, peptide-MHC; r.m.s.d., root mean square distance; SPR, surface plasmon resonance; vdw, van der Waals.

© 2009 Archbold et al.
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