A structural basis for immunodominant human T cell receptor recognition.
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)). V(beta)17V(alpha)10.2 T cell receptors (TCRs) containing a conserved arginine-serine-serine sequence in complementarity determining region 3 (CDR3) of the V(beta) segment dominate this response. To investigate the molecular basis of immunodominant selection in an outbred population, we have determined the crystal structure of V(beta)17V(alpha)10.2 in complex with MP(58-66)-HLA-A2 at a resolution of 1.4 A. 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 V(beta)17V(alpha)10.2, which is almost orthogonal to the peptide-binding groove of HLA-A2, facilitates insertion of the conserved arginine in V(beta) CDR3 into a notch in the surface of MP(58-66)-HLA-A2. This previously unknown binding mode underlies the immunodominant T cell response.
Stewart-Jones
Guillaume B E
GB
Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, UK.
McMichael
Andrew J
AJ
Bell
John I
JI
Stuart
David I
DI
Jones
E Yvonne
EY
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D022801:Complementarity Determining Regions; D003460:Crystallization; D015789:HLA-A2 Antigen / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D009975:Orthomyxoviridae / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry* / Q000276:immunology; D014763:Viral Matrix Proteins / Q000737:chemistry*
D022801:Complementarity Determining Regions; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014763:Viral Matrix Proteins