Deficient activation and resistance to activation-induced apoptosis of CD8+ T cells is associated with defective peripheral tolerance in nonobese diabetic mice

Clin Immunol. 2003 May;107(2):103-15. doi: 10.1016/s1521-6616(03)00049-4.


Activation-induced cell death (AICD) is a mechanism of homeostasis that limits the clonal expansion of autoreactive T cells and regulates central and peripheral tolerance. In nonobese diabetic (NOD) mice, defects in central and peripheral tolerance are associated with a proliferative hyporesponsiveness of thymocytes and peripheral T cells elicited upon TCR activation. We investigated whether these defects in tolerance induction and hyporesponsiveness of NOD T cells manifest in an altered susceptibility to TCR-induced AICD. TCR-activated NOD splenic CD4+ and CD8+ T cells are more resistant to AICD than control strain C57BL/6, BALB/c, and NOR T cells. NOR CD4+ but not CD8+ T cells are resistant to TCR-induced AICD. Whereas c-FLIP expression is reduced in activated T cells from control strains, it persists in activated NOD CD8+ T cells and is accompanied by diminished activity of caspase-3 and -8. IL-4 reduces this c-FLIP expression and increases caspase-3 and -8 activity in activated NOD CD8+ T cells. Moreover, IL-4 and CD28 costimulation restores the susceptibility of NOD CD8+ T cells to AICD, and this is associated with increased expression of CD25, CD95, CD95L, and TNFR2. Thus, deficient activation of CD8+ T cells and their greater resistance to TCR-induced AICD may mediate defective peripheral tolerance and the development of T1D in NOD mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / immunology
  • Antigens, CD / metabolism
  • Apoptosis / immunology*
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / biosynthesis
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases / immunology
  • Caspases / metabolism
  • Diabetes Mellitus, Type 1 / immunology*
  • Enzyme Activation
  • Female
  • Immune Tolerance / immunology*
  • Interleukin-2 / pharmacology
  • Interleukin-4 / immunology
  • Interleukin-4 / metabolism
  • Intracellular Signaling Peptides and Proteins*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Receptors, Antigen, T-Cell / immunology
  • Specific Pathogen-Free Organisms


  • Antigens, CD
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins
  • Cflar protein, mouse
  • Interleukin-2
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Antigen, T-Cell
  • Interleukin-4
  • Casp3 protein, mouse
  • Casp8 protein, mouse
  • Casp9 protein, mouse
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases