Title |
An Extensive Antigenic Footprint Underpins Immunodominant TCR Adaptability against a Hypervariable Viral Determinant
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Published in |
The Journal of Immunology, December 2014
|
DOI | 10.4049/jimmunol.1401357 |
Pubmed ID | |
Authors |
Usha K Nivarthi, Stephanie Gras, Lars Kjer-Nielsen, Richard Berry, Isabelle S Lucet, John J Miles, Samantha L Tracy, Anthony W Purcell, David S Bowden, Margaret Hellard, Jamie Rossjohn, James McCluskey, Mandvi Bharadwaj |
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. |
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Geographical breakdown
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Demographic breakdown
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Student > Ph. D. Student | 6 | 15% |
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Veterinary Science and Veterinary Medicine | 1 | 2% |
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