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Cell. 2019 May 30;177(6):1583-1599.e16. doi: 10.1016/j.cell.2019.05.007.

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

Author information

1
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3
Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA.
4
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
5
Barbara Davis Center for Diabetes, University of Colorado, Aurora, CO 80045, USA.
6
Department of Molecular Biology and Genetics and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
7
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
8
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
9
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
10
Department of Molecular Biology and Genetics and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
11
Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA; Department of Chemistry, Columbia University, New York, NY 10027, USA. Electronic address: rz24@columbia.edu.
12
Department of Biochemistry and Nutrition, Des Moines University, Des Moines, IA 50312, USA.
13
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: ahamad@jhmi.edu.

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.

KEYWORDS:

DEs; autoantigen; dual expressers; insulin mimotope; islet autoantigen; type 1 diabetes; x-clonotype; x-idiotype

PMID:
31150624
DOI:
10.1016/j.cell.2019.05.007

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