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2 Gene Underlies the IL-12 Unresponsiveness of Lps-Defective C57BL/10ScCr Mice1
*
The Scripps Research Institute, La Jolla, CA 92037; and
Max-Planck-Institut für Immunbiologie, Freiburg, Germany
Lps-defective C57BL/10ScCr (Cr) mice
are homozygous for a deletion encompassing Toll-like receptor
4 that makes them refractory to the biological activity of LPS.
In addition, these mice exhibit an inherited IL-12 unresponsiveness
resulting in impaired IFN-
responses to different microorganisms. By
positional cloning methods, we show here that this second defect of Cr
mice is due to a mutation in a single gene located on mouse chromosome
6, in close proximity to the Ig
locus. The gene is
IL-12R
2. Cr mice carry a point mutation creating a
stop codon that is predicted to cause premature termination of the
translated IL-12R2 after a lysine residue at position 777. The
truncated 2 chain can still form a heterodimeric IL-12R that allows
phosphorylation of Janus kinase 2, but, unlike the wild-type IL-12R,
can no longer mediate phosphorylation of STAT4. Because the
phosphorylation of STAT4 is a prerequisite for the IL-12-mediated
induction of IFN-, its absence in Cr mice is responsible for their
defective IFN- response to microorganisms.
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