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

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.

• Authors: Rahel Frick, Lene S Høydahl, Jan Petersen, M Fleur du Pré, Shraddha Kumari, Grete Berntsen, Alisa E Dewan, Jeliazko R Jeliazkov, Kristin S Gunnarsen, Terje Frigstad, Erik S Vik, Carmen Llerena, Knut E A Lundin, Sheraz Yaqub, Jørgen Jahnsen, Jeffrey J Gray, Jamie Rossjohn, Ludvig M Sollid, Inger Sandlie, Geir Åge Løset
• Journal: Science immunology (Sci Immunol) Vol. 6 Issue 62 (08 20 2021) ISSN: 2470-9468 [Electronic] United States
• PMID: 34417258 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Epitopes, T-Lymphocyte
• HLA-DQ Antigens
• HLA-DQ2 antigen
• Peptides
• Receptors, Antigen, T-Cell
• Glutens

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology)
• Celiac Disease (immunology)
• Cell Line, Tumor
• Epitopes, T-Lymphocyte (immunology)
• Glutens (chemistry, immunology)
• HLA-DQ Antigens (chemistry, immunology)
• Humans
• Lymphocyte Activation (immunology)
• Mice
• Models, Molecular
• Peptides (chemistry, immunology)
• Receptors, Antigen, T-Cell (chemistry, immunology)