title: Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition.
abstract: 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.
authors.affiliation: The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Archbold
authors.forename: Whitney A
authors.initials: WA
authors.lastname: Macdonald
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gras
authors.forename: Lauren K
authors.initials: LK
authors.lastname: Ely
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Bell
authors.forename: Rebekah M
authors.initials: RM
authors.lastname: Brennan
authors.forename: Travis
authors.initials: T
authors.lastname: Beddoe
authors.forename: Matthew C J
authors.initials: MC
authors.lastname: Wilce
authors.forename: Craig S
authors.initials: CS
authors.lastname: Clements
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D022801:Complementarity Determining Regions / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics / Q000378:metabolism; D015235:HLA-B Antigens / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D059948:HLA-B44 Antigen; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D022801:Complementarity Determining Regions; D018984:Epitopes, T-Lymphocyte; D019309:Epstein-Barr Virus Nuclear Antigens; D006680:HLA Antigens; D015235:HLA-B Antigens; C495439:HLA-B*44:03 antigen; D059948:HLA-B44 Antigen; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011994:Recombinant Proteins