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

Nivarthi, Usha K., Gras, Stephanie, Kjer-Nielsen, Lars, Berry, Richard, Lucet, Isabelle S., Miles, John J., Tracy, Samantha L., Purcell, Anthony W., Bowden, David S., Hellard, Margaret, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, McCluskey, James and Bharadwaj, Mandvi 2014. An extensive antigenic footprint underpins immunodominant TCR adaptability against a hypervariable viral determinant. The Journal of Immunology 193 (11) , pp. 5402-5413. 10.4049/jimmunol.1401357

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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 (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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > QR Microbiology > QR180 Immunology
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Date of Acceptance:	26 September 2014
Last Modified:	31 Oct 2022 09:01
URI:	https://orca.cardiff.ac.uk/id/eprint/79575

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