Inherent ER stress in pancreatic islet β cells causes self-recognition by autoreactive T cells in type 1 diabetes

J Autoimmun. 2016 Aug;72:33-46. doi: 10.1016/j.jaut.2016.04.009. Epub 2016 May 9.


Type 1 diabetes (T1D) is an autoimmune disease characterized by pancreatic β cell destruction induced by islet reactive T cells that have escaped central tolerance. Many physiological and environmental triggers associated with T1D result in β cell endoplasmic reticulum (ER) stress and dysfunction, increasing the potential for abnormal post-translational modification (PTM) of proteins. We hypothesized that β cell ER stress induced by environmental and physiological conditions generates abnormally-modified proteins for the T1D autoimmune response. To test this hypothesis we exposed the murine CD4(+) diabetogenic BDC2.5 T cell clone to murine islets in which ER stress had been induced chemically (Thapsigargin). The BDC2.5 T cell IFNγ response to these cells was significantly increased compared to non-treated islets. This β cell ER stress increased activity of the calcium (Ca(2+))-dependent PTM enzyme tissue transglutaminase 2 (Tgase2), which was necessary for full stress-dependent immunogenicity. Indeed, BDC2.5 T cells responded more strongly to their antigen after its modification by Tgase2. Finally, exposure of non-antigenic murine insulinomas to chemical ER stress in vitro or physiological ER stress in vivo caused increased ER stress and Tgase2 activity, culminating in higher BDC2.5 responses. Thus, β cell ER stress induced by chemical and physiological triggers leads to β cell immunogenicity through Ca(2+)-dependent PTM. These findings elucidate a mechanism of how β cell proteins are modified and become immunogenic, and reveal a novel opportunity for preventing β cell recognition by autoreactive T cells.

Keywords: Autoimmunity; ER stress; Post-translational modification; Type 1 diabetes; β cell.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Autoantigens / genetics
  • Autoantigens / immunology
  • Autoimmunity / genetics
  • Autoimmunity / immunology*
  • Blotting, Western
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Calcium / immunology
  • Calcium / metabolism
  • Cell Line
  • Cells, Cultured
  • Chromogranin A / genetics
  • Chromogranin A / immunology
  • Chromogranin A / metabolism
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Endoplasmic Reticulum Stress / genetics
  • Endoplasmic Reticulum Stress / immunology*
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / immunology
  • GTP-Binding Proteins / metabolism
  • Humans
  • Insulin-Secreting Cells / immunology*
  • Insulin-Secreting Cells / metabolism
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Models, Immunological
  • Protein Processing, Post-Translational / immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tandem Mass Spectrometry
  • Transglutaminases / genetics
  • Transglutaminases / immunology
  • Transglutaminases / metabolism


  • Autoantigens
  • Chromogranin A
  • transglutaminase 2
  • Transglutaminases
  • GTP-Binding Proteins
  • Calcium