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T cell receptor interactions with human leukocyte antigen govern indirect peptide selectivity for the cancer testis antigen MAGE-A4

DOI: 10.1074/jbc.RA120.014016 DOI Help

Authors: Charlotte Coles (Immunocore Ltd) , Catriona Mcmurran (Immunocore Ltd) , Angharad Lloyd (Immunocore Ltd) , Miriam Hock (Immunocore Ltd) , Linda Hibbert (Immunocore Ltd) , Marine C. C. Raman (Immunocore Ltd) , Conor Hayes (Immunocore Ltd) , Patrick Lupardus (Genetech, Inc) , David K. Cole (Immunocore Ltd) , Stephen Harper (Immunocore Ltd)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry

State: Published (Approved)
Published: June 2020
Diamond Proposal Number(s): 17077

Abstract: T cell-mediated immunity is governed primarily by T cell receptor (TCR) recognition of peptide human leukocyte antigen complexes (pHLA) and is essential for immunosurveillance and disease control. This interaction is generally stabilised by interactions between the HLA surface and TCR germline encoded complementarity determining region (CDR) loops 1 and 2, whereas peptide selectivity is guided by direct interactions with the TCR CDR3 loops. Here, we solved the structure of a newly identified TCR in complex with a clinically relevant peptide derived from the cancer testis antigen melanoma antiGEn-A4 (MAGE-A4). The TCR bound pHLA in a position shifted toward the peptide’s N-terminus. This enabled the TCR to achieve peptide selectivity via an indirect mechanism, whereby the TCR sensed the first residue of the peptide through HLA residue Trp167, which acted as a tuneable gateway. Amino acid substitutions at peptide position 1 predicted to alter the HLA Trp167 sidechain conformation abrogated TCR binding, indicating that this indirect binding mechanism is essential for peptide recognition. These findings extend our understanding of the molecular rules that underpin antigen recognition by TCRs and have important implications for the development of TCR-based therapies.

Journal Keywords: peptide-human leukocyte antigen; cancer associated antigen; MAGE-A4; T cell receptor; antigen recognition; immunotherapy; cancer therapy; surface plasmon resonance (SPR); antigen presentation; crystal structure

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

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