Extinction of IL-12 signaling promotes Fas-mediated apoptosis of antigen-specific T cells.
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.
Marth
T
T
Internal Medicine II, University of the Saarland, Homburg/Saar, Germany.
Zeitz
M
M
Ludviksson
B R
BR
Strober
W
W
Kelsall
B L
BL
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D017637:Clonal Deletion; D004768:Enterotoxins / Q000008:administration & dosage; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D007106:Immune Sera / Q000008:administration & dosage / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D010581:Peyer's Patches / Q000166:cytology / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D004768:Enterotoxins; D018984:Epitopes, T-Lymphocyte; D007106:Immune Sera; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D018664:Interleukin-12; C031818:enterotoxin B, staphylococcal; D010047:Ovalbumin