A molecular basis for the interplay between T cells, viral mutants, and human leukocyte antigen micropolymorphism.
Mutations within T cell epitopes represent a common mechanism of viral escape from the host 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 (407)HPVGEADYFEY(417) epitope from Epstein-Barr virus 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 Epstein-Barr virus.
From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Melbourne 3800, Australia.
Yu Chih
YC
Liu
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia.
Zhenjun
Z
Chen
QIMR Berghofer Medical Research Institute and QIMR Berghofer Centre for Immunotherapy and Vaccine Development, Brisbane, Queensland 4006, Australia.
Michelle A
MA
Neller
QIMR Berghofer Medical Research Institute and QIMR Berghofer Centre for Immunotherapy and Vaccine Development, Brisbane, Queensland 4006, Australia.
John J
JJ
Miles
From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Melbourne 3800, Australia.
Anthony W
AW
Purcell
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia.
James
J
McCluskey
QIMR Berghofer Medical Research Institute and QIMR Berghofer Centre for Immunotherapy and Vaccine Development, Brisbane, Queensland 4006, Australia.
Scott R
SR
Burrows
From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Melbourne 3800, Australia, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN Wales, United Kingdom, and Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia jamie.rossjohn@monash.edu.
Jamie
J
Rossjohn
From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Melbourne 3800, Australia, Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia stephanie.gras@monash.edu.
Stephanie
S
Gras
D000483:Alleles; D000595:Amino Acid Sequence; D000939:Epitopes / Q000737:chemistry / Q000235:genetics; D015797:HLA-B35 Antigen / Q000737:chemistry* / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000276:immunology; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology
D000939:Epitopes; C500431:HLA-B*35:01 antigen; D015797:HLA-B35 Antigen; D011948:Receptors, Antigen, T-Cell
Immunology; Major Histocompatibility Complex (MHC); Structural Biology; T Cell Receptor (TCR); X-ray Crystallography