Abstract
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
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Amino Acid Substitution
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Antibody Affinity
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Antibody Diversity
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Antigen-Antibody Complex / chemistry
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Antigen-Antibody Complex / genetics
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Antigen-Antibody Complex / metabolism
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Antigens, Viral / chemistry
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Antigens, Viral / genetics
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Antigens, Viral / metabolism*
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Clonal Deletion
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Epitopes, T-Lymphocyte / chemistry
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Epitopes, T-Lymphocyte / genetics
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Epitopes, T-Lymphocyte / metabolism*
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HLA-A2 Antigen / chemistry
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HLA-A2 Antigen / genetics
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HLA-A2 Antigen / metabolism*
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Humans
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Hydrogen Bonding
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Immunodominant Epitopes / chemistry
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Immunodominant Epitopes / genetics
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Immunodominant Epitopes / metabolism*
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Influenza A virus / immunology
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Influenza A virus / metabolism
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Models, Molecular*
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Mutation
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Peptide Fragments / chemistry
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Peptide Fragments / metabolism
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Protein Conformation
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Protein Conformation, alpha-Helical
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Receptors, Antigen, T-Cell, alpha-beta / chemistry
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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Receptors, Antigen, T-Cell, alpha-beta / metabolism*
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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T-Cell Antigen Receptor Specificity
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T-Lymphocytes, Cytotoxic / cytology
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / metabolism
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T-Lymphocytes, Cytotoxic / virology
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Viral Matrix Proteins / chemistry
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Viral Matrix Proteins / genetics
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Viral Matrix Proteins / metabolism*
Substances
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Antigen-Antibody Complex
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Antigens, Viral
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Epitopes, T-Lymphocyte
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HLA-A2 Antigen
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Immunodominant Epitopes
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M1 protein, Influenza A virus
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Peptide Fragments
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Receptors, Antigen, T-Cell, alpha-beta
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Recombinant Proteins
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Viral Matrix Proteins
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influenza matrix peptide (58-66)
Associated data
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PDB/1OGA
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PDB/5ISZ
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PDB/5JHD
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PDB/5TEZ
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PDB/5EUO
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PDB/1BD2
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PDB/1LP9
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PDB/1MI5
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PDB/2BNQ
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PDB/2BNR
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PDB/2E7L
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PDB/2YPL
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PDB/3VXR
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PDB/5D2N
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PDB/3VXU