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) |
|---|---|
| Pages (from-to) | 1583-1599.e16 |
| Journal | Cell |
| Volume | 177 |
| Issue number | 6 |
| DOIs | |
| State | Published - May 30 2019 |
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Keywords
- autoantigen
- DEs
- dual expressers
- insulin mimotope
- islet autoantigen
- type 1 diabetes
- x-clonotype
- x-idiotype
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
A Public BCR Present in a Unique Dual-Receptor-Expressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen. / Ahmed, Rizwan; Omidian, Zahra; Giwa, Adebola; Cornwell, Benjamin; Majety, Neha; Bell, David R.; Lee, Sangyun; Zhang, Hao; Michels, Aaron; Desiderio, Stephen; Sadegh-Nasseri, Scheheraza; Rabb, Hamid; Gritsch, Simon; Suva, Mario L.; Cahan, Patrick; Zhou, Ruhong; Jie, Chunfa; Donner, Thomas W; Hamad, Abdel R.
In: Cell, Vol. 177, No. 6, 30.05.2019, p. 1583-1599.e16.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A Public BCR Present in a Unique Dual-Receptor-Expressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen
AU - Ahmed, Rizwan
AU - Omidian, Zahra
AU - Giwa, Adebola
AU - Cornwell, Benjamin
AU - Majety, Neha
AU - Bell, David R.
AU - Lee, Sangyun
AU - Zhang, Hao
AU - Michels, Aaron
AU - Desiderio, Stephen
AU - Sadegh-Nasseri, Scheheraza
AU - Rabb, Hamid
AU - Gritsch, Simon
AU - Suva, Mario L.
AU - Cahan, Patrick
AU - Zhou, Ruhong
AU - Jie, Chunfa
AU - Donner, Thomas W
AU - Hamad, Abdel R
PY - 2019/5/30
Y1 - 2019/5/30
N2 - 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.
AB - 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.
KW - autoantigen
KW - DEs
KW - dual expressers
KW - insulin mimotope
KW - islet autoantigen
KW - type 1 diabetes
KW - x-clonotype
KW - x-idiotype
UR - http://www.scopus.com/inward/record.url?scp=85065609284&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065609284&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2019.05.007
DO - 10.1016/j.cell.2019.05.007
M3 - Article
C2 - 31150624
AN - SCOPUS:85065609284
VL - 177
SP - 1583-1599.e16
JO - Cell
JF - Cell
SN - 0092-8674
IS - 6
ER -