Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition

Julia Kate Archbold, Whitney Alison Macdonald, Stephanie Gras, Lauren Kate Ely, John J Miles, Melissa J Bell, Rebekah M Brennan, Travis Clarke Beddoe, Matthew Charles James Wilce, Craig Steven Clements, Anthony Wayne Purcell, James McCluskey, Scott R Burrows, Jamie Rossjohn

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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
Original languageEnglish
Pages (from-to)209 - 219
Number of pages11
JournalJournal of Experimental Medicine
Issue number1
Publication statusPublished - 2009

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