A heritable defect in IL-12 signaling in B10.Q/J mice. I. In vitro analysis

B10.Q mice are normally susceptible to the induction of collagen-induced ar thritis. We noted that one subline of B10.Q mice, B10.Q/J, was completely r esistant 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-specif ic 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 activa ted 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 t o 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, activ ated T cells from B10.Q/j mice did not signal normally through the IL-12R a nd manifested a defect in their capacity to phosphorylate Stat4. This defec t was partial in that it could be overcome by increasing both the concentra tion 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. Thi s subtle abnormality in IL-12 responsiveness results in a profound defect i n the generation of Th1 cells and the development of autoimmune disease.