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

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.

UR - http://www.jimmunol.org/content/193/11/5402.full.pdf+html

U2 - 10.4049/jimmunol.1401357

DO - 10.4049/jimmunol.1401357

M3 - Article

VL - 193

SP - 5402

EP - 5413

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 11

ER -