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A molecular basis for the interplay between T cells, viral mutants and human leukocyte antigen micropolymorphism

Liu, Yu Chih, Chen, Zhenjun, Neller, Michelle A., Miles, John J,, Purcell, Anthony W., McCluskey, James, Burrows, Scott R., Rossjohn, Jamie and Gras, Stephanie 2014. A molecular basis for the interplay between T cells, viral mutants and human leukocyte antigen micropolymorphism. The Journal of Biological Chemistry 289 (24) , pp. 16688-98. 10.1074/jbc.M114.563502

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Mutations within T cell epitopes represent a common mechanism of viral escape from the host's protective immune response. The diverse T cell repertoire and the extensive human leukocyte antigen (HLA) polymorphism across populations is the evolutionary response to viral mutation. However, the molecular basis underpinning the interplay between HLA polymorphism, the T cell repertoire and viral escape is unclear. Here, we investigate the T cell response to a HLA-B*35:01 and HLA-B*35:08 restricted 407HPVGEADYFEY417 epitope (HPVG) from Epstein-Barr virus (EBV), and naturally occurring variants at positions 4 and 5 thereof. Each viral variant differently impacted on the epitope's flexibility and conformation when bound to HLA-B*35:08 or HLA-B*35:01. We provide a molecular basis for understanding how the single residue polymorphism that discriminates between HLA-B*35:01/08 profoundly impacts on T cell receptor recognition. Surprisingly, one viral variant (P5-Glu to P5-Asp) effectively changed restriction preference from HLA-B*35:01 to HLA-B*35:08. Collectively, our study portrays the interplay between the T cell response, viral escape and HLA polymorphism, whereby HLA polymorphism enables altered presentation of epitopes from different strains of EBV.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: immunology; major histocompatibility complex (MHC); structural biology; T-cell receptor (TCR); X-ray crystallography
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 1083-351X
Date of Acceptance: 23 April 2014
Last Modified: 04 Jun 2017 09:07

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