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, Scheherazade Sadegh-Nasseri, Hamid Rabb, Simon Gritsch, Mario L. Suva, Patrick Cahan, Ruhong Zhou, Chunfa Jie, Thomas Donner, Abdel Rahim A. 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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Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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