Abstract
The anti-influenza CD8+ T cell response in HLA-A2–positive adults is almost exclusively directed at residues 58–66 of the virus matrix protein (MP(58–66)). Vβ17Vα10.2 T cell receptors (TCRs) containing a conserved arginine-serine-serine sequence in complementarity determining region 3 (CDR3) of the Vβ segment dominate this response. To investigate the molecular basis of immunodominant selection in an outbred population, we have determined the crystal structure of Vβ17Vα10.2 in complex with MP(58–66)–HLA-A2 at a resolution of 1.4 Å. We show that, whereas the TCR typically fits over an exposed side chain of the peptide, in this structure MP(58–66) exposes only main chain atoms. This distinctive orientation of Vβ17Vα10.2, which is almost orthogonal to the peptide-binding groove of HLA-A2, facilitates insertion of the conserved arginine in Vβ CDR3 into a notch in the surface of MP(58–66)–HLA-A2. This previously unknown binding mode underlies the immunodominant T cell response.
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Acknowledgements
We thank K. Harlos and the staff of the ESRF and the European Molecular Biology Laboratory outstation at Grenoble for assistance with data collection. This work was funded by the MRC. D.I.S. is an MRC Research Professor and E.Y.J. is a Cancer Research UK Principal Research Fellow.
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Stewart-Jones, G., McMichael, A., Bell, J. et al. A structural basis for immunodominant human T cell receptor recognition. Nat Immunol 4, 657–663 (2003). https://doi.org/10.1038/ni942
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DOI: https://doi.org/10.1038/ni942
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