Format

Send to:

Choose Destination
See comment in PubMed Commons below
J Immunol. 2014 Dec 1;193(11):5402-13. doi: 10.4049/jimmunol.1401357. Epub 2014 Oct 29.

An extensive antigenic footprint underpins immunodominant TCR adaptability against a hypervariable viral determinant.

Author information

  • 1Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3000, Australia;
  • 2Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia;
  • 3Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia;
  • 4Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom; Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia; School of Medicine, University of Queensland, Brisbane, Queensland 4006, Australia;
  • 5Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3000, Australia;
  • 6Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia;
  • 7Centre for Population Health, Burnet Institute, Melbourne, Victoria 3004, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria 3800, Australia; and Centre for Research Excellence into Injecting Drug Use, Burnet Institute, Melbourne, Victoria 3004, Australia.
  • 8Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia; Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom; mandvi@unimelb.edu.au jamesm1@unimelb.edu.au Jamie.Rossjohn@monash.edu.
  • 9Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3000, Australia; mandvi@unimelb.edu.au jamesm1@unimelb.edu.au Jamie.Rossjohn@monash.edu.

Abstract

Mutations in T cell epitopes are implicated in hepatitis C virus (HCV) persistence and can impinge on vaccine development. We recently demonstrated a narrow bias in the human TCR repertoire targeted at an immunodominant, but highly mutable, HLA-B*0801-restricted epitope ((1395)HSKKKCDEL(1403) [HSK]). To investigate if the narrow TCR repertoire facilitates CTL escape, structural and biophysical studies were undertaken, alongside comprehensive functional analysis of T cells targeted at the natural variants of HLA-B*0801-HSK in different HCV genotypes and quasispecies. Interestingly, within the TCR-HLA-B*0801-HSK complex, the TCR contacts all available surface-exposed residues of the HSK determinant. This broad epitope coverage facilitates cross-genotypic reactivity and recognition of common mutations reported in HCV quasispecies, albeit to a varying degree. Certain mutations did abrogate T cell reactivity; however, natural variants comprising these mutations are reportedly rare and transient in nature, presumably due to fitness costs. Overall, despite a narrow bias, the TCR accommodated frequent mutations by acting like a blanket over the hypervariable epitope, thereby providing effective viral immunity. Our findings simultaneously advance the understanding of anti-HCV immunity and indicate the potential for cross-genotype HCV vaccines.

Copyright © 2014 by The American Association of Immunologists, Inc.

PMID:
25355921
[PubMed - indexed for MEDLINE]
Free full text
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire
    Loading ...
    Write to the Help Desk