Structural basis for clonal diversity of the human T-cell response to a dominant influenza virus epitope

J Biol Chem. 2017 Nov 10;292(45):18618-18627. doi: 10.1074/jbc.M117.810382. Epub 2017 Sep 20.


Influenza A virus (IAV) causes an acute infection in humans that is normally eliminated by CD8+ cytotoxic T lymphocytes. Individuals expressing the MHC class I molecule HLA-A2 produce cytotoxic T lymphocytes bearing T-cell receptors (TCRs) that recognize the immunodominant IAV epitope GILGFVFTL (GIL). Most GIL-specific TCRs utilize α/β chain pairs encoded by the TRAV27/TRBV19 gene combination to recognize this relatively featureless peptide epitope (canonical TCRs). However, ∼40% of GIL-specific TCRs express a wide variety of other TRAV/TRBV combinations (non-canonical TCRs). To investigate the structural underpinnings of this remarkable diversity, we determined the crystal structure of a non-canonical GIL-specific TCR (F50) expressing the TRAV13-1/TRBV27 gene combination bound to GIL-HLA-A2 to 1.7 Å resolution. Comparison of the F50-GIL-HLA-A2 complex with the previously published complex formed by a canonical TCR (JM22) revealed that F50 and JM22 engage GIL-HLA-A2 in markedly different orientations. These orientations are distinguished by crossing angles of TCR to peptide-MHC of 29° for F50 versus 69° for JM22 and by a focus by F50 on the C terminus rather than the center of the MHC α1 helix for JM22. In addition, F50, unlike JM22, uses a tryptophan instead of an arginine to fill a critical notch between GIL and the HLA-A2 α2 helix. The F50-GIL-HLA-A2 complex shows that there are multiple structurally distinct solutions to recognizing an identical peptide-MHC ligand with sufficient affinity to elicit a broad anti-IAV response that protects against viral escape and T-cell clonal loss.

Keywords: T-cell receptor; crystal structure; epitope; influenza virus; major histocompatibility complex (MHC); protein complex; surface plasmon resonance (SPR).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Substitution
  • Antibody Affinity
  • Antibody Diversity
  • Antigen-Antibody Complex / chemistry
  • Antigen-Antibody Complex / genetics
  • Antigen-Antibody Complex / metabolism
  • Antigens, Viral / chemistry
  • Antigens, Viral / genetics
  • Antigens, Viral / metabolism*
  • Clonal Deletion
  • Epitopes, T-Lymphocyte / chemistry
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / metabolism*
  • HLA-A2 Antigen / chemistry
  • HLA-A2 Antigen / genetics
  • HLA-A2 Antigen / metabolism*
  • Humans
  • Hydrogen Bonding
  • Immunodominant Epitopes / chemistry
  • Immunodominant Epitopes / genetics
  • Immunodominant Epitopes / metabolism*
  • Influenza A virus / immunology
  • Influenza A virus / metabolism
  • Models, Molecular*
  • Mutation
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Protein Conformation
  • Protein Conformation, alpha-Helical
  • Receptors, Antigen, T-Cell, alpha-beta / chemistry
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • T-Cell Antigen Receptor Specificity
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism
  • T-Lymphocytes, Cytotoxic / virology
  • Viral Matrix Proteins / chemistry
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / metabolism*


  • Antigen-Antibody Complex
  • Antigens, Viral
  • Epitopes, T-Lymphocyte
  • HLA-A2 Antigen
  • Immunodominant Epitopes
  • M1 protein, Influenza A virus
  • Peptide Fragments
  • Receptors, Antigen, T-Cell, alpha-beta
  • Recombinant Proteins
  • Viral Matrix Proteins
  • influenza matrix peptide (58-66)

Associated data

  • PDB/1OGA
  • PDB/5ISZ
  • PDB/5JHD
  • PDB/5TEZ
  • PDB/5EUO
  • PDB/1BD2
  • PDB/1LP9
  • PDB/1MI5
  • PDB/2BNQ
  • PDB/2BNR
  • PDB/2E7L
  • PDB/2YPL
  • PDB/3VXR
  • PDB/5D2N
  • PDB/3VXU