Extinction of IL-12 signaling promotes Fas-mediated apoptosis of antigen-specific T cells

J Immunol. 1999 Jun 15;162(12):7233-40.


In previous studies we have shown that peripheral tolerance achieved by high dose feeding of OVA to intact OVA-TCR transgenic mice was enhanced when endogenous IL-12 was neutralized simultaneously. To generalize this phenomenon, in the present study we investigated the tolerogenic mechanisms underlying the blockade of IL-12 signaling following oral and systemic Ag delivery. We found that the numbers of Ag-specific T cells in several lymphoid organs were significantly reduced due to T cell apoptosis following oral OVA or systemic OVA administration when combined with anti-IL-12 injection, but there was no decrease in T cell numbers for OVA-fed, OVA-injected, or anti-IL-12 alone-treated mice compared with those in untreated control mice. In addition, mostly Fas+ T cells were subject to apoptotic deletion in the OVA- plus anti-IL-12-treated groups, and an enhanced cell death of T cells upon OVA restimulation in vitro could be partially reversed by blockade of the Fas/Fas ligand interaction. Finally, in a murine model of superantigen-driven T cell expansion and deletion, we observed no deletional effects of anti-IL-12 treatment on CD4+ cells in Fas-deficient (MRL/lpr) mice, but did find these effects in MRL wild-type mice. In summary, our data suggest that in the course of Ag-induced cell proliferation of Th1 cells, signaling through IL-12 is required to prevent an induction of Fas-mediated apoptosis. Thus, the use of anti-IL-12 may be potentially useful in modulating peripheral immune responses by promotion of Fas-mediated cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology*
  • Cells, Cultured
  • Clonal Deletion
  • Enterotoxins / administration & dosage
  • Epitopes, T-Lymphocyte / immunology*
  • Immune Sera / administration & dosage
  • Immune Sera / pharmacology
  • Injections, Intraperitoneal
  • Interleukin-12 / antagonists & inhibitors*
  • Interleukin-12 / immunology
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred MRL lpr
  • Mice, Transgenic
  • Ovalbumin / administration & dosage
  • Ovalbumin / genetics
  • Ovalbumin / immunology
  • Peyer's Patches / cytology
  • Peyer's Patches / immunology
  • Receptors, Antigen, T-Cell / genetics
  • Signal Transduction / immunology*
  • Spleen / cytology
  • Spleen / immunology
  • Staphylococcus aureus / immunology
  • T-Lymphocyte Subsets / cytology*
  • T-Lymphocyte Subsets / immunology
  • fas Receptor / biosynthesis
  • fas Receptor / genetics
  • fas Receptor / physiology*


  • Enterotoxins
  • Epitopes, T-Lymphocyte
  • Immune Sera
  • Receptors, Antigen, T-Cell
  • fas Receptor
  • Interleukin-12
  • enterotoxin B, staphylococcal
  • Ovalbumin