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Laboratories of
*
Immunology and
Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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-
. Because T cells from these mice could
produce normal amounts of IFN- 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- when stimulated by IL-12. The capacity of NK cells,
but not activated T cells, to produce IFN- in response to IL-12
could be partially restored by IL-18. The expression of the IL-12R
1- and 2-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.
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