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

Rizwan Ahmed, Zahra Omidian, Adebola Giwa, Benjamin Cornwell, Neha Majety, David R. Bell, Sangyun Lee, Hao Zhang, Aaron Michels, Stephen Desiderio, Scheheraza Sadegh-Nasseri, Hamid Rabb, Simon Gritsch, Mario L. Suva, Patrick Cahan, Ruhong Zhou, Chunfa Jie, Thomas W Donner, Abdel R Hamad

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)1583-1599.e16
JournalCell
Volume177
Issue number6
DOIs
StatePublished - May 30 2019

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T-cells
Lymphocytes
Autoantigens
Medical problems
Type 1 Diabetes Mellitus
T-Lymphocytes
B-Lymphocytes
Bearings (structural)
Cells
Peptides
Molecular dynamics
Molecular Dynamics Simulation
Autoimmunity
Binding Sites
Insulin
Autoimmune Diseases
Antigens
Computer simulation

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 journalArticle

Ahmed, R, Omidian, Z, Giwa, A, Cornwell, B, Majety, N, Bell, DR, Lee, S, Zhang, H, Michels, A, Desiderio, S, Sadegh-Nasseri, S, Rabb, H, Gritsch, S, Suva, ML, Cahan, P, Zhou, R, Jie, C, Donner, TW & Hamad, AR 2019, 'A Public BCR Present in a Unique Dual-Receptor-Expressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen', Cell, vol. 177, no. 6, pp. 1583-1599.e16. https://doi.org/10.1016/j.cell.2019.05.007
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. / A Public BCR Present in a Unique Dual-Receptor-Expressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen. In: Cell. 2019 ; Vol. 177, No. 6. pp. 1583-1599.e16.
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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

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