Journal article

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 J Miles, Samantha L Tracy, Anthony W Purcell, David S Bowden, Margaret Hellard, Jamie Rossjohn, James McCluskey, Mandvi Bharadwaj



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 determ..

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Funding Acknowledgements

This work was supported by a Networks project grant and program grant of the National Health and Medical Research Council of Australia (NHMRC), grants from the Australian Research Council, and a grant from the Roche Organ Transplantation Research Foundation. S.G. is supported by an Australian Research Council Future Fellowship. R.B. is supported by an NHMRC Training Fellowship. J.J.M. is supported by an NHMRC Career Development Fellowship. M.H. and A.W.P. are supported by NHMRC Senior Research Fellowships. J.R. was supported by an NHMRC Australia Fellowship.