A Public BCR Present in a Unique Dual-Receptor-Expressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen

• Published in: Cell 2019-05, Vol.177 (6), p.1583-1599.e16
• Main Authors: Ahmed, Rizwan, Omidian, Zahra, Giwa, Adebola, Cornwell, Benjamin, Majety, Neha, Bell, David R., Lee, Sangyun, Zhang, Hao, Michels, Aaron, Desiderio, Stephen, Sadegh-Nasseri, Scheherazade, Rabb, Hamid, Gritsch, Simon, Suva, Mario L., Cahan, Patrick, Zhou, Ruhong, Jie, Chunfa, Donner, Thomas, Hamad, Abdel Rahim A.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; autoantigen; Autoantigens - immunology; B-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - immunology; Child; Child, Preschool; DEs; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - metabolism; dual expressers; Epitopes - immunology; Female; HEK293 Cells; HLA-DQ Antigens - immunology; HLA-DQ Antigens - ultrastructure; Humans; insulin mimotope; islet autoantigen; Lymphocyte Activation - immunology; Lymphocytes - immunology; Lymphocytes - metabolism; Male; Middle Aged; Molecular Dynamics Simulation; Peptides; Protein Binding - immunology; type 1 diabetes; x-clonotype; x-idiotype
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2019.05.007

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. [Display omitted] •Dual expressers (DEs) are new lymphocytes that coexpress functional BCR and TCR•A single BCR clonotype (x-clonotype) predominates DEs in T1D subjects•x-clonotype encodes a potent autoantigen with an optimal register for HLA-DQ8•x-mAb secreted by DEs is a potent stimulator of insulin-specific CD4 T cells 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.