@article{40699ec034eb4342a7f3dccace03cda4,
title = "A Public BCR Present in a Unique Dual-Receptor-Expressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen",
abstract = "T and B cells are the two known lineages of adaptive immune cells. Here, we describe a previously unknown lymphocyte that is a dual expresser (DE) of TCR and BCR and key lineage markers of both B and T cells. In type 1 diabetes (T1D), DEs are predominated by one clonotype that encodes a potent CD4 T cell autoantigen in its antigen binding site. Molecular dynamics simulations revealed that this peptide has an optimal binding register for diabetogenic HLA-DQ8. In concordance, a synthetic version of the peptide forms stable DQ8 complexes and potently stimulates autoreactive CD4 T cells from T1D patients, but not healthy controls. Moreover, mAbs bearing this clonotype are autoreactive against CD4 T cells and inhibit insulin tetramer binding to CD4 T cells. Thus, compartmentalization of adaptive immune cells into T and B cells is not absolute, and violators of this paradigm are likely key drivers of autoimmune diseases. Type I diabetes patients have unique TCR- and BCR-positive lymphocytes, in which a public BCR encodes a potent autoantigen that stimulates autologous CD4 T cells and may contribute to autoimmunity.",
keywords = "DEs, autoantigen, dual expressers, insulin mimotope, islet autoantigen, type 1 diabetes, x-clonotype, x-idiotype",
author = "Rizwan Ahmed and Zahra Omidian and Adebola Giwa and Benjamin Cornwell and Neha Majety and Bell, {David R.} and Sangyun Lee and Hao Zhang and Aaron Michels and Stephen Desiderio and Scheherazade Sadegh-Nasseri and Hamid Rabb and Simon Gritsch and Suva, {Mario L.} and Patrick Cahan and Ruhong Zhou and Chunfa Jie and Thomas Donner and Hamad, {Abdel Rahim A.}",
note = "Funding Information: We thank participants enrolled in this study and their families for their blood donation. Special thanks to Sarah Longenecker of Johns Hopkins for recruiting and consenting subjects and the NIH Tetramer Core Facility for providing DQ8 monomers. We thank Dr. Katie Boland of Adaptive Biotechnologies (Seattle, WA) for depositing the immuno-seq data to immuneACCESS Data—Adaptive Biotechnologies. We thank Norman Barker of Pathology Photography, Digital Imaging, & Computer Graphics at Johns Hopkins Medicine for production of gel images and Jinglong Ding and Michelle Beaucher from ThermoFisher Scientific for imaging DE clones using the EVOS M7000 Imagine System. Special thanks to Dr. Joseph Margolick, Director of Flor Cytometry Core at the Bloomberg School of Public Health. This work was supported by NIH, United States, grant R0 AI099027 (A.R.A.H.) and the Norman Raab Foundation, United States. A.G. is supported by NIH, United States T32HD044355. A.R.A.H. conceived the project and wrote the original manuscript. R.A. and A.R.A.H. designed experiments and interpreted data. R.A. performed experiments, analyzed data, prepared figures, and co-wrote the manuscript. B.C. performed experiments, analyzed data, and prepared tables for immuno-seq data. H.Z. sorted DEs and conventional B and T cells for high-throughput immune-seq and sorted single DEs and B and T cells for scRNA-seq. A.M. H.R. and S.D. provided reagents and critically reviewed and edited the manuscript. D.R.B, S.L. and R.Z. designed, performed, analyzed, wrote, and interpreted the MDS simulations. Z.O. with the help of R.A. cloned and expressed BCR and TCR from DE cells. A.G. recruited donors, prepared PBMC samples, and critically read and edited the manuscript, graphic abstract, and Excel sheets. N.M. contributed to Excel-sheet preparation and editing of the Graphical Abstract. M.S. and S.G. performed scRNA-seq. S.S.-N. supervised peptide-binding experiments. P.C. and C.J. did differential gene expression and reconstruction, prepared heatmaps from scRNA-seq, and reconstructed BCR and TCR using scRNA-seq data. C.J. performed statistical analysis of immuno-seq data. T.D. recruited donors and discussed, critically reviewed, and edited the manuscript. The authors declare no conflict of interests. Funding Information: We thank participants enrolled in this study and their families for their blood donation. Special thanks to Sarah Longenecker of Johns Hopkins for recruiting and consenting subjects and the NIH Tetramer Core Facility for providing DQ8 monomers. We thank Dr. Katie Boland of Adaptive Biotechnologies (Seattle, WA) for depositing the immuno-seq data to immuneACCESS Data?Adaptive Biotechnologies. We thank Norman Barker of Pathology Photography, Digital Imaging, & Computer Graphics at Johns Hopkins Medicine for production of gel images and Jinglong Ding and Michelle Beaucher from ThermoFisher Scientific for imaging DE clones using the EVOS M7000 Imagine System. Special thanks to Dr. Joseph Margolick, Director of Flor Cytometry Core at the Bloomberg School of Public Health. This work was supported by NIH, United States, grant R0 AI099027 (A.R.A.H.) and the Norman Raab Foundation, United States. A.G. is supported by NIH, United States T32HD044355. A.R.A.H. conceived the project and wrote the original manuscript. R.A. and A.R.A.H. designed experiments and interpreted data. R.A. performed experiments, analyzed data, prepared figures, and co-wrote the manuscript. B.C. performed experiments, analyzed data, and prepared tables for immuno-seq data. H.Z. sorted DEs and conventional B and T cells for high-throughput immune-seq and sorted single DEs and B and T cells for scRNA-seq. A.M. H.R. and S.D. provided reagents and critically reviewed and edited the manuscript. D.R.B, S.L. and R.Z. designed, performed, analyzed, wrote, and interpreted the MDS simulations. Z.O. with the help of R.A. cloned and expressed BCR and TCR from DE cells. A.G. recruited donors, prepared PBMC samples, and critically read and edited the manuscript, graphic abstract, and Excel sheets. N.M. contributed to Excel-sheet preparation and editing of the Graphical Abstract. M.S. and S.G. performed scRNA-seq. S.S.-N. supervised peptide-binding experiments. P.C. and C.J. did differential gene expression and reconstruction, prepared heatmaps from scRNA-seq, and reconstructed BCR and TCR using scRNA-seq data. C.J. performed statistical analysis of immuno-seq data. T.D. recruited donors and discussed, critically reviewed, and edited the manuscript. The authors declare no conflict of interests. Funding Information: We thank participants enrolled in this study and their families for their blood donation. Special thanks to Sarah Longenecker of Johns Hopkins for recruiting and consenting subjects and the NIH Tetramer Core Facility for providing DQ8 monomers. We thank Dr. Katie Boland of Adaptive Biotechnologies (Seattle, WA) for depositing the immuno-seq data to immuneACCESS Data—Adaptive Biotechnologies. We thank Norman Barker of Pathology Photography, Digital Imaging, & Computer Graphics at Johns Hopkins Medicine for production of gel images and Jinglong Ding and Michelle Beaucher from ThermoFisher Scientific for imaging DE clones using the EVOS M7000 Imagine System. Special thanks to Dr. Joseph Margolick, Director of Flor Cytometry Core at the Bloomberg School of Public Health. This work was supported by NIH , United States, grant R0 AI099027 (A.R.A.H.) and the Norman Raab Foundation , United States. A.G. is supported by NIH , United States T32HD044355 . Publisher Copyright: {\textcopyright} 2019",
year = "2019",
month = may,
day = "30",
doi = "10.1016/j.cell.2019.05.007",
language = "English (US)",
volume = "177",
pages = "1583--1599.e16",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",
}