Efficacy of clonal deletion vs. anergy of self-reactive CD4 T-cells for the prevention and reversal of autoimmune diabetes

J Autoimmun. 2005 Aug;25(1):21-32. doi: 10.1016/j.jaut.2005.04.003.


The self-reactive CD4 T-cells play an essential role in triggering and sustaining organ-specific autoimmune diseases. Silencing or elimination of these cells can prevent and reverse an autoimmune process. We have previously showed that a single dose-administration of a soluble dimeric MHC II-peptide chimera (DEF) in double-transgenic mice delayed the onset autoimmune diabetes, and restored the euglycemia in already diabetic mice for a period of 1 week. DEF dimer protection relied on induction of anergy of diabetogenic CD4 T-cells in spleen, and stimulation of IL-10-secreting T regulatory type 1 cells in pancreas. Herein, we show that an octameric form of DEF has doubled the period of protection and reversal of disease by clonal deletion of diabetogenic CD4 T-cells in both the thymic and peripheral compartments. Deletion occurred by activation-induced cell death subsequent to repartitioning and signaling of FAS-FADD apoptotic module in the plasma membrane lipid rafts. Our previous and present data indicated first, that DEF valence translates into various effects on the antigen-specific CD4 T-cells, i.e., Th2 immune deviation, anergy, and apoptosis. Second, the present findings argue for a better efficacy of clonal deletion than anergy of diabetogenic CD4 T-cells for the protection and reversal of autoimmune diabetes.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • Cell Death / genetics
  • Cell Death / immunology
  • Cell Membrane / immunology
  • Cells, Cultured
  • Clonal Anergy / immunology*
  • Clonal Deletion / immunology*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 1 / prevention & control*
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / therapeutic use
  • Membrane Microdomains / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Peptides / genetics
  • Peptides / therapeutic use
  • Prediabetic State / genetics
  • Prediabetic State / immunology
  • Prediabetic State / pathology
  • Prediabetic State / prevention & control
  • Rats
  • Recombinant Fusion Proteins / therapeutic use
  • Signal Transduction / immunology
  • Thymus Gland / cytology
  • Thymus Gland / immunology


  • Histocompatibility Antigens Class II
  • Peptides
  • Recombinant Fusion Proteins