A high-affinity human TCR-like antibody detects celiac disease gluten peptide-MHC complexes and inhibits T cell activation.

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  • Additional Information
    • Source:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101688624 Publication Model: Print Cited Medium: Internet ISSN: 2470-9468 (Electronic) Linking ISSN: 24709468 NLM ISO Abbreviation: Sci Immunol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : American Association for the Advancement of Science, [2016]-
    • Subject Terms:
      CD4-Positive T-Lymphocytes/*immunology ; Celiac Disease/*immunology ; Glutens/*immunology ; HLA-DQ Antigens/*immunology ; Peptides/*immunology ; Receptors, Antigen, T-Cell/*immunology; Animals ; Cell Line, Tumor ; Epitopes, T-Lymphocyte/immunology ; Glutens/chemistry ; HLA-DQ Antigens/chemistry ; Humans ; Lymphocyte Activation/immunology ; Mice ; Models, Molecular ; Peptides/chemistry ; Receptors, Antigen, T-Cell/chemistry
    • Abstract:
      Antibodies specific for peptides bound to human leukocyte antigen (HLA) molecules are valuable tools for studies of antigen presentation and may have therapeutic potential. Here, we generated human T cell receptor (TCR)-like antibodies toward the immunodominant signature gluten epitope DQ2.5-glia-α2 in celiac disease (CeD). Phage display selection combined with secondary targeted engineering was used to obtain highly specific antibodies with picomolar affinity. The crystal structure of a Fab fragment of the lead antibody 3.C11 in complex with HLA-DQ2.5:DQ2.5-glia-α2 revealed a binding geometry and interaction mode highly similar to prototypic TCRs specific for the same complex. Assessment of CeD biopsy material confirmed disease specificity and reinforced the notion that abundant plasma cells present antigen in the inflamed CeD gut. Furthermore, 3.C11 specifically inhibited activation and proliferation of gluten-specific CD4 + T cells in vitro and in HLA-DQ2.5 humanized mice, suggesting a potential for targeted intervention without compromising systemic immunity.
      (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
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    • Grant Information:
      R01 GM078221 United States GM NIGMS NIH HHS
    • Accession Number:
      0 (Epitopes, T-Lymphocyte)
      0 (HLA-DQ Antigens)
      0 (HLA-DQ2 antigen)
      0 (Peptides)
      0 (Receptors, Antigen, T-Cell)
      8002-80-0 (Glutens)
    • Publication Date:
      Date Created: 20210821 Date Completed: 20220228 Latest Revision: 20220228
    • Publication Date:
      20240829
    • Accession Number:
      PMC8670751
    • Accession Number:
      10.1126/sciimmunol.abg4925
    • Accession Number:
      34417258