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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.","bibjson":{"author":[{"initials":"JK","lastname":"Archbold","name":"Archbold JK"},{"initials":"WA","lastname":"Macdonald","name":"Macdonald WA"},{"initials":"S","lastname":"Gras","name":"Gras S"},{"initials":"LK","lastname":"Ely","name":"Ely LK"},{"initials":"JJ","lastname":"Miles","name":"Miles JJ"},{"initials":"MJ","lastname":"Bell","name":"Bell MJ"},{"initials":"RM","lastname":"Brennan","name":"Brennan RM"},{"initials":"T","lastname":"Beddoe","name":"Beddoe T"},{"initials":"MC","lastname":"Wilce","name":"Wilce MC"},{"initials":"CS","lastname":"Clements","name":"Clements CS"},{"initials":"AW","lastname":"Purcell","name":"Purcell AW"},{"initials":"J","lastname":"McCluskey","name":"McCluskey J"},{"initials":"SR","lastname":"Burrows","name":"Burrows SR"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"}],"identifier":[{"id":"10.1084/jem.20082136","type":"doi"},{"id":"19139173","type":"pubmed"}],"issue":["1"],"journal":{"iso_abbreviation":"J. 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