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

Usha K Nivarthi, Stephanie Gras, Lars Kjer-Nielsen, Richard Berry, Isabelle S Lucet, John Miles, Samantha Lilly Tracy, Anthony W Purcell, David S Bowden, Margaret E Hellard, Jamie Rossjohn, James McCluskey, Mandvi Bharadwaj

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)5402 - 5413
Number of pages12
JournalJournal of Immunology
Volume193
Issue number11
DOIs
Publication statusPublished - 2014

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