Extinction of IL-12 Signaling Promotes Fas-Mediated Apoptosis of Antigen-Specific T Cells

• Published in: The Journal of immunology (1950) 1999-06, Vol.162 (12), p.7233-7240
• Main Authors: Marth, Thomas, Zeitz, Martin, Ludviksson, Bjorn R, Strober, Warren, Kelsall, Brian L
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Apoptosis - genetics; Apoptosis - immunology; Cells, Cultured; Clonal Deletion; Enterotoxins - administration & dosage; Epitopes, T-Lymphocyte - immunology; fas Receptor - biosynthesis; fas Receptor - genetics; fas Receptor - physiology; 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
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.162.12.7233

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.