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 (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.

Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses

“…6C supplying cells sequenced in Table III), we conclude that TCRB CDR3 amino acids contribute to differential recognition of the HSV and VZV peptide variants. This is consistent with crystal structures of TCR-HLA-peptide (76, 77). We are testing the hypothesis that TCRA CDR3 sequences may be similar for mono- and cross-reactive cells.…”

Crystal structure of the giant panda MHC class I complex: First insights into the viral peptide presentation profile in the bear family

“…Ternary TCR-peptide-HLA-B*0801 structure of epitope HCV-HSK9 (HSKKKCDEL, hepatitis C virus-derived) showed that the protruding residue Lys-4 in HCV-HSK9 plays important roles in TCR recognition. 31,32 In pAime-128, the side chain of P6-Phe pointed upward for solvent exposure, similar to the side chain of Lys-4 in HCV-HSK9 (Figure 4a,b).…”

Crystal structure of the giant panda MHC class I complex: first insights into the viral peptide presentation profile in the bear family

“…Extensive comparison of pAime-128 with other pMHC-I structures deposited in the Protein Data Bank showed that the main chain of the CCV-NGY9 peptide has a characteristic conformation similar to that presented by HLA-B*0801 ( Fig 4B ). Ternary TCR-peptide-HLA-B*0801 structure of epitope HCV-HSK9 (HSKKKCDEL, hepatitis C virus-derived) showed that the protruding residue Lys-4 in HCV-HSK9 plays important roles in TCR recognition (31, 32). In pAime-128, the side chain of P6-Phe pointed upward for solvent exposure, similar to the side chain of Lys-4 in HCV-HSK9 ( Fig 4A and B ).…”