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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autoantigens / immunology
  • B-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Epitopes / immunology
  • Female
  • HEK293 Cells
  • HLA-DQ Antigens / immunology
  • HLA-DQ Antigens / ultrastructure
  • Humans
  • Lymphocyte Activation / immunology
  • Lymphocytes / immunology
  • Lymphocytes / metabolism
  • Male
  • Middle Aged
  • Molecular Dynamics Simulation
  • Peptides
  • Protein Binding / immunology

Substances

  • Autoantigens
  • Epitopes
  • HLA-DQ Antigens
  • HLA-DQ8 antigen
  • Peptides