An Extensive Antigenic Footprint Underpins Immunodominant TCR Adaptability against a Hypervariable Viral Determinant
| Autor: | Samantha Lilly Tracy, Mandvi Bharadwaj, Richard Berry, Isabelle S Lucet, Margaret Hellard, D. S. Bowden, Lars Kjer-Nielsen, Jamie Rossjohn, Stephanie Gras, Usha K Nivarthi, Anthony W. Purcell, John J. Miles, James McCluskey |
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| Rok vydání: | 2014 |
| Předmět: |
Cytotoxicity
Immunologic Protein Conformation T cell Immunology Receptors Antigen T-Cell Epitopes T-Lymphocyte Hepacivirus Viral quasispecies CD8-Positive T-Lymphocytes Viral Nonstructural Proteins Crystallography X-Ray Protein Engineering Major histocompatibility complex medicine.disease_cause Epitope HLA-B8 Antigen Structure-Activity Relationship MHC class I medicine Antigenic variation Humans Immunology and Allergy Cells Cultured Genetics Mutation biology Immunodominant Epitopes Protein Stability T-cell receptor Antigenic Variation Hepatitis C Virology Peptide Fragments medicine.anatomical_structure biology.protein Protein Binding |
| Zdroj: | The Journal of Immunology. 193:5402-5413 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1401357 |
| Popis: | 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 (1395HSKKKCDEL1403 [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. |
| Databáze: | OpenAIRE |
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