Biochemistry and Pharmacology - Research Publications

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Author: McCluskey, James × Author: Rossjohn, Jamie × End date: 2009 × Start date: 2000 × Type: Journal Article ×

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    Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition
    Archbold, JK ; Macdonald, WA ; Gras, S ; Ely, LK ; Miles, JJ ; Bell, MJ ; Brennan, RM ; Beddoe, T ; Wilce, MCJ ; Clements, CS ; Purcell, AW ; McCluskey, J ; Burrows, SR ; Rossjohn, J (ROCKEFELLER UNIV PRESS, 2009-01-16)
    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.
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    The immunogenicity of a viral cytotoxic T cell epitope is controlled by its MHC-bound conformation
    Tynan, FE ; Elhassen, D ; Purcell, AW ; Burrows, JM ; Borg, NA ; Miles, JJ ; Williamson, NA ; Green, KJ ; Tellam, J ; Kjer-Nielsen, L ; McCluskey, J ; Rossjohn, J ; Burrows, SR (ROCKEFELLER UNIV PRESS, 2005-11-07)
    Thousands of potentially antigenic peptides are encoded by an infecting pathogen; however, only a small proportion induce measurable CD8(+) T cell responses. To investigate the factors that control peptide immunogenicity, we have examined the cytotoxic T lymphocyte (CTL) response to a previously undefined epitope ((77)APQPAPENAY(86)) from the BZLF1 protein of Epstein-Barr virus (EBV). This peptide binds well to two human histocompatibility leukocyte antigen (HLA) allotypes, HLA-B*3501 and HLA-B*3508, which differ by a single amino acid at position 156 ((156)Leucine vs. (156)Arginine, respectively). Surprisingly, only individuals expressing HLA-B*3508 show evidence of a CTL response to the (77)APQPAPENAY(86) epitope even though EBV-infected cells expressing HLA-B*3501 process and present similar amounts of peptide for CTL recognition, suggesting that factors other than peptide presentation levels are influencing immunogenicity. Functional and structural analysis revealed marked conformational differences in the peptide, when bound to each HLA-B35 allotype, that are dictated by the polymorphic HLA residue 156 and that directly affected T cell receptor recognition. These data indicate that the immunogenicity of an antigenic peptide is influenced not only by how well the peptide binds to major histocompatibility complex (MHC) molecules but also by its bound conformation. It also illustrates a novel mechanism through which MHC polymorphism can further diversify the immune response to infecting pathogens.