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

Frick, Rahel, Høydahl, Lene S., Petersen, Jan, du Pré, M. Fleur, Kumari, Shraddha, Berntsen, Grete, Dewan, Alisa E., Jeliazkov, Jeliazko R., Gunnarsen, Kristin S., Frigstad, Terje, Vik, Erik S., Llerena, Carmen, Lundin, Knut E.A., Yaqub, Sheraz, Jahnsen, Jørgen, Gray, Jeffrey J., Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Sollid, Ludvig M., Sandlie, Inger and Løset, Geir Åge 2021. A high-affinity human TCR-like antibody detects celiac disease gluten peptide-MHC complexes and inhibits T cell activation. Science Immunology 6 (62) , eabg4925. 10.1126/sciimmunol.abg4925

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	American Association for the Advancement of Science
ISSN:	2470-9468
Date of First Compliant Deposit:	14 March 2025
Date of Acceptance:	22 July 2021
Last Modified:	18 Mar 2025 13:30
URI:	https://orca.cardiff.ac.uk/id/eprint/176883

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