A high-affinity human TCR-like antibody detects celiac disease gluten peptide-MHC complexes and inhibits T cell activation
| Autor: | Kristin Støen Gunnarsen, Inger Sandlie, M. Fleur du Pré, Knut E.A. Lundin, Jeliazko R. Jeliazkov, Geir Åge Løset, Ludvig M. Sollid, Alisa E. Dewan, Jamie Rossjohn, Rahel Frick, Lene Støkken Høydahl, Sheraz Yaqub, Grete Berntsen, Jan Petersen, Carmen Llerena, Terje Frigstad, Erik S. Vik, Jeffrey J. Gray, Shraddha Kumari, Jørgen Jahnsen |
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| Rok vydání: | 2021 |
| Předmět: |
CD4-Positive T-Lymphocytes
Models Molecular Phage display Glutens T cell Immunology Antigen presentation Receptors Antigen T-Cell Epitopes T-Lymphocyte Human leukocyte antigen Lymphocyte Activation Epitope Article Mice Antigen Cell Line Tumor HLA-DQ Antigens medicine Animals Humans biology Chemistry T-cell receptor nutritional and metabolic diseases General Medicine Molecular biology Celiac Disease medicine.anatomical_structure biology.protein Antibody Peptides |
| Zdroj: | Sci Immunol |
| ISSN: | 2470-9468 |
| Popis: | 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 towards 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. Further, 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. ONE SENTENCE SUMMARY: A human TCR-like antibody blocks gluten-dependent activation of celiac disease T-cells in vitro and in HLA-DQ2.5 humanized mice. |
| Databáze: | OpenAIRE |
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