IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes

J Clin Invest. 2000 Feb;105(4):459-68. doi: 10.1172/JCI8185.


Cytokines such as IL-1alpha, IL-1beta, and IFN-gamma have long been implicated in the pathogenesis of autoimmune diabetes, but the mechanisms through which they promote diabetogenesis remain unclear. Here we show that CD4(+) T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice expressing the highly diabetogenic, beta cell-specific 4.1-T-cell receptor (4.1-TCR) can kill IL-1alpha-, IL-1beta-, and IFN-gamma-treated beta cells from NOD mice. Untreated NOD beta cells and cytokine-treated beta cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of islet cells in vitro was associated with cytokine-induced upregulation of Fas on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR-transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4(+) T cells or with their ability to cause insulitis. In contrast, abrogation of perforin expression did not affect beta cell-specific cytotoxicity or the diabetogenic potential of these T cells. These data demonstrate a novel mechanism of action of IL-1alpha, IL-1beta, and IFN-gamma in autoimmune diabetes, whereby these cytokines mark beta cells for Fas-dependent lysis by autoreactive CD4(+) T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Differentiation
  • Cell Line
  • Chromium Radioisotopes / metabolism
  • Cytokines / metabolism*
  • Diabetes Mellitus, Experimental / etiology
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Type 1 / etiology*
  • Fas Ligand Protein
  • Female
  • Histocompatibility Antigens Class I
  • Interferon-gamma / metabolism
  • Interleukin-1 / metabolism
  • Islets of Langerhans / cytology
  • Islets of Langerhans / immunology
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred MRL lpr
  • Mice, Inbred NOD
  • Mice, Mutant Strains
  • Pancreatitis
  • Perforin
  • Pore Forming Cytotoxic Proteins
  • Spleen / cytology
  • Spleen / immunology
  • T-Lymphocytes, Cytotoxic


  • Chromium Radioisotopes
  • Cytokines
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Histocompatibility Antigens Class I
  • Interleukin-1
  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Perforin
  • Interferon-gamma