How punctual ablation of regulatory T cells unleashes an autoimmune lesion within the pancreatic islets

Immunity. 2009 Oct 16;31(4):654-64. doi: 10.1016/j.immuni.2009.08.023. Epub 2009 Oct 8.


CD4(+)Foxp3(+) regulatory T cells (Treg cells) are known to control the progression of autoimmune diabetes, but when, where, and how they exert their influence in this context are questions still under vigorous debate. Exploiting a transgene encoding the human diphtheria toxin receptor, we punctually and specifically ablated Foxp3(+) cells in the BCD2.5/NOD mouse model of autoimmune diabetes. Strikingly, overt disease developed within 3 days. The earliest detectable event was the activation of natural killer (NK) cells directly within the insulitic lesion, particularly the induction of Ifng gene expression within 7 hours of Treg cell ablation. Interferon-gamma had a strong impact on the gene-expression program of the local CD4(+) T effector cell population, unleashing it to aggressively attack the islets, which was required for the development of diabetes. Thus, Treg cells regulate pancreatic autoimmunity in situ through control of a central innate immune system player, NK cells.

Publication types

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

MeSH terms

  • Animals
  • Autoimmunity
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / pathology
  • Humans
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Lymphocyte Depletion
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism


  • Interferon-gamma