PMID- 34417258 OWN - NLM STAT- MEDLINE DCOM- 20220228 LR - 20220228 IS - 2470-9468 (Electronic) IS - 2470-9468 (Linking) VI - 6 IP - 62 DP - 2021 Aug 20 TI - A high-affinity human TCR-like antibody detects celiac disease gluten peptide-MHC complexes and inhibits T cell activation. LID - 10.1126/sciimmunol.abg4925 [doi] LID - eabg4925 AB - 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-alpha2 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-alpha2 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. CI - Copyright (c) 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. FAU - Frick, Rahel AU - Frick R AUID- ORCID: 0000-0002-3469-5686 AD - Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway. AD - Centre for Immune Regulation and Department of Biosciences, University of Oslo, Oslo, Norway. FAU - Hoydahl, Lene S AU - Hoydahl LS AUID- ORCID: 0000-0001-6070-1413 AD - Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway. AD - Centre for Immune Regulation and Department of Biosciences, University of Oslo, Oslo, Norway. AD - KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway. FAU - Petersen, Jan AU - Petersen J AUID- ORCID: 0000-0002-2045-6342 AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. AD - Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. FAU - du Pre, M Fleur AU - du Pre MF AD - Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway. AD - KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway. FAU - Kumari, Shraddha AU - Kumari S AD - Nextera AS, Oslo, Norway. FAU - Berntsen, Grete AU - Berntsen G AUID- ORCID: 0000-0002-8920-9200 AD - Nextera AS, Oslo, Norway. FAU - Dewan, Alisa E AU - Dewan AE AUID- ORCID: 0000-0001-7314-5778 AD - Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway. AD - KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway. FAU - Jeliazkov, Jeliazko R AU - Jeliazkov JR AUID- ORCID: 0000-0003-4249-1955 AD - Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD, USA. FAU - Gunnarsen, Kristin S AU - Gunnarsen KS AUID- ORCID: 0000-0002-1124-5535 AD - Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway. AD - Centre for Immune Regulation and Department of Biosciences, University of Oslo, Oslo, Norway. FAU - Frigstad, Terje AU - Frigstad T AD - Nextera AS, Oslo, Norway. FAU - Vik, Erik S AU - Vik ES AD - Nextera AS, Oslo, Norway. FAU - Llerena, Carmen AU - Llerena C AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. FAU - Lundin, Knut E A AU - Lundin KEA AUID- ORCID: 0000-0003-1713-5545 AD - Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway. AD - KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway. AD - Department of Gastroenterology, Oslo University Hospital-Rikshospitalet, Oslo, Norway. FAU - Yaqub, Sheraz AU - Yaqub S AUID- ORCID: 0000-0002-5696-2319 AD - Department of Gastrointestinal Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway. AD - Institute of Clinical Medicine, University of Oslo, Oslo, Norway. FAU - Jahnsen, Jorgen AU - Jahnsen J AUID- ORCID: 0000-0002-0419-2914 AD - Institute of Clinical Medicine, University of Oslo, Oslo, Norway. AD - Department of Gastroenterology, Akershus University Hospital, Lorenskog, Norway. FAU - Gray, Jeffrey J AU - Gray JJ AUID- ORCID: 0000-0001-6380-2324 AD - Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD, USA. AD - Department of Chemical and Biomolecular Engineering and Institute of NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA. AD - Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA. FAU - Rossjohn, Jamie AU - Rossjohn J AUID- ORCID: 0000-0002-2020-7522 AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. AD - Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. AD - Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK. FAU - Sollid, Ludvig M AU - Sollid LM AUID- ORCID: 0000-0001-8860-704X AD - Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway. AD - KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway. FAU - Sandlie, Inger AU - Sandlie I AD - Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway. AD - Centre for Immune Regulation and Department of Biosciences, University of Oslo, Oslo, Norway. FAU - Loset, Geir Age AU - Loset GA AUID- ORCID: 0000-0002-5257-8571 AD - Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway. galoset@nextera.no. AD - Centre for Immune Regulation and Department of Biosciences, University of Oslo, Oslo, Norway. AD - Nextera AS, Oslo, Norway. LA - eng GR - R01 GM078221/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Sci Immunol JT - Science immunology JID - 101688624 RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (HLA-DQ Antigens) RN - 0 (HLA-DQ2 antigen) RN - 0 (Peptides) RN - 0 (Receptors, Antigen, T-Cell) RN - 8002-80-0 (Glutens) SB - IM MH - Animals MH - CD4-Positive T-Lymphocytes/*immunology MH - Celiac Disease/*immunology MH - Cell Line, Tumor MH - Epitopes, T-Lymphocyte/immunology MH - Glutens/chemistry/*immunology MH - HLA-DQ Antigens/chemistry/*immunology MH - Humans MH - Lymphocyte Activation/immunology MH - Mice MH - Models, Molecular MH - Peptides/chemistry/*immunology MH - Receptors, Antigen, T-Cell/chemistry/*immunology PMC - PMC8670751 MID - NIHMS1747441 EDAT- 2021/08/22 06:00 MHDA- 2022/03/01 06:00 PMCR- 2022/02/20 CRDT- 2021/08/21 05:34 PHST- 2021/01/11 00:00 [received] PHST- 2021/07/22 00:00 [accepted] PHST- 2021/08/21 05:34 [entrez] PHST- 2021/08/22 06:00 [pubmed] PHST- 2022/03/01 06:00 [medline] PHST- 2022/02/20 00:00 [pmc-release] AID - 6/62/eabg4925 [pii] AID - 10.1126/sciimmunol.abg4925 [doi] PST - ppublish SO - Sci Immunol. 2021 Aug 20;6(62):eabg4925. doi: 10.1126/sciimmunol.abg4925.