title: A heritable defect in IL-12 signaling in B10.Q/J mice. I. In vitro analysis.
abstract: B10.Q mice are normally susceptible to the induction of collagen-induced arthritis. We noted that one subline of B10.Q mice, B10.Q/J, was completely resistant to disease induction when immunized with collagen in CFA. B10.Q/J mice have a global defect in the generation of Th1 responses, and Ag-specific T cells derived from this strain failed to produce IFN-gamma. Because T cells from these mice could produce normal amounts of IFN-gamma when activated by IL-12/IL-18-independent stimuli, the defect appeared to be a failure to respond to IL-12. This defect extended to NK cells, which also failed to produce IFN-gamma when stimulated by IL-12. The capacity of NK cells, but not activated T cells, to produce IFN-gamma in response to IL-12 could be partially restored by IL-18. The expression of the IL-12R beta1- and beta2-chains on T cells and NK cells from B10.Q/J mice was normal. However, activated T cells from B10.Q/J mice did not signal normally through the IL-12R and manifested a defect in their capacity to phosphorylate Stat4. This defect was partial in that it could be overcome by increasing both the concentration of IL-12 and the incubation times in the Stat4 phosphorylation assays. Because Stat4 function is apparently intact in B10.Q/J mice, the defect in IL-12 signaling can be localized between the IL-12R complex and Stat4. This subtle abnormality in IL-12 responsiveness results in a profound defect in the generation of Th1 cells and the development of autoimmune disease.
authors: Laboratories of. Immunology and Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: R
authors: R
authors: Ortmann
authors: R
authors: R
authors: Smeltz
authors: G
authors: G
authors: Yap
authors: A
authors: A
authors: Sher
authors: E M
authors: EM
authors: Shevach
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004357:Drug Synergism; D020022:Genetic Predisposition to Disease; D006183:H-2 Antigens / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D018664:Interleukin-12 / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D020382:Interleukin-18 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics*; D010766:Phosphorylation; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000502:physiology; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D006183:H-2 Antigens; C508440:Il12rb1 protein, mouse; C508443:Il12rb2 protein, mouse; D020382:Interleukin-18; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma