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.
Original language | English (US) |
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Pages (from-to) | 1583-1599.e16 |
Journal | Cell |
Volume | 177 |
Issue number | 6 |
DOIs | |
State | Published - May 30 2019 |
Keywords
- DEs
- autoantigen
- dual expressers
- insulin mimotope
- islet autoantigen
- type 1 diabetes
- x-clonotype
- x-idiotype
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology