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

UK Nivarthi, S Gras, L Kjer-Nielsen, R Berry… - The Journal of …, 2014 - journals.aai.org
UK Nivarthi, S Gras, L Kjer-Nielsen, R Berry, IS Lucet, JJ Miles, SL Tracy, AW Purcell
The Journal of Immunology, 2014journals.aai.org
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 …
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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