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in Th1 Differentiation: IFN- Regulates IL-18R
Expression by Preventing the Negative Effects of IL-4 and by Inducing/Maintaining IL-12 Receptor 
2 Expression
* Laboratory of Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, Bethesda, MD 20814; and
Bioseek, Burlingame, CA 94010
Two key events occur during the differentiation of
IFN-
-secreting Th1 cells: up-regulation of IL-12R
2 and
IL-12-driven up-regulation of IL-18R
. We previously demonstrated
that IL-12-driven up-regulation of IL-18R expression is severely
impaired in IFN--/- mice. However, it was unclear from
these studies how IFN- influenced IL-18R since IFN- alone had
no direct effect on IL-18R expression. In the absence of IL-4,
IL-12-dependent up-regulation of IL-18R/IL-12R2 was independent
of IFN-. However, in the presence of IL-4, IFN- functions to
limit the negative effects of IL-4 on both IL-18R and IL-12R2.
Neutralization of IL-4 restored IL-12-driven up-regulation of
IL-18R/IL-12R2 in an IFN--independent fashion. In the absence
of both IL-12 and IL-4, IFN- up-regulates IL-122 expression and
primes IFN--producing Th1 cells. When T cells were primed in the
presence of IL-4, no correlation was found between the levels of
expression of the IL-18R or the IL-12R2 and the capacity of these
cells to produce IFN-, suggesting that IL-4 may also negatively
affect IL-12-mediated signal transduction and thus Th1 differentiation.
These data clarify the role of IFN- in regulation of
IL-18R/IL-12R2 during both IL-12-dependent and IL-12-independent
Th1 differentiation.
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