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

Cite this

@article{2c6ec4800c574fafae8c8fffb45d8abc,
title = "An extensive antigenic footprint underpins immunodominant TCR adaptability against a hypervariable viral determinant",
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.",
author = "Nivarthi, {Usha K} and Stephanie Gras and Lars Kjer-Nielsen and Richard Berry and Lucet, {Isabelle S} and John Miles and Tracy, {Samantha Lilly} and Purcell, {Anthony W} and Bowden, {David S} and Hellard, {Margaret E} and Jamie Rossjohn and James McCluskey and Mandvi Bharadwaj",
year = "2014",
doi = "10.4049/jimmunol.1401357",
language = "English",
volume = "193",
pages = "5402 -- 5413",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "11",

}

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; Tracy, Samantha Lilly; Purcell, Anthony W; Bowden, David S; Hellard, Margaret E; Rossjohn, Jamie; McCluskey, James; Bharadwaj, Mandvi.

In: Journal of Immunology, Vol. 193, No. 11, 2014, p. 5402 - 5413.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - An extensive antigenic footprint underpins immunodominant TCR adaptability against a hypervariable viral determinant

AU - Nivarthi, Usha K

AU - Gras, Stephanie

AU - Kjer-Nielsen, Lars

AU - Berry, Richard

AU - Lucet, Isabelle S

AU - Miles, John

AU - Tracy, Samantha Lilly

AU - Purcell, Anthony W

AU - Bowden, David S

AU - Hellard, Margaret E

AU - Rossjohn, Jamie

AU - McCluskey, James

AU - Bharadwaj, Mandvi

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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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