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

Publication Type:

Journal Article


J Biol Chem, Volume 292, Issue 45, p.18618-18627 (2017)


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


<p>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, &sim;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&deg; for F50 69&deg; 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.</p>