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 ORCID: https://orcid.org/0000-0002-2020-7522 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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Abstract

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:	01 Nov 2022 10:13
URI:	https://orca.cardiff.ac.uk/id/eprint/90733

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