ARTICLE: A Public BCR Present in a Unique Dual-Receptor-Expressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen
AUTHORS: Rizwan Ahmed, Zahra Omidian, Adebola Giwa, Benjamin Cornwell, Neha Majety, David R. Bell, Sangyun Lee, Hao Zhang, Aaron Michels, Stephen Desiderio, Scheherazade Sadegh-Nasseri, Hamid Rabb, Simon Gritsch, Mario L. Suva, Patrick Cahan, Ruhong Zhou, Chunfa Jie, Thomas Donner, Abdel Rahim A. Hamad
JOURNAL: Cell. 2019 May 30;177(6):1583-1599.e16. doi: 10.1016/j.cell.2019.05.007.
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.
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