IL-12 receptor β2 (IL-12Rβ2)-deficient mice are defective in IL-12-mediated signaling despite the presence of high affinity IL-12 binding sites

C Wu, X Wang, M Gadina, JJ O'Shea… - The Journal of …, 2000 - journals.aai.org
C Wu, X Wang, M Gadina, JJ O'Shea, DH Presky, J Magram
The Journal of Immunology, 2000journals.aai.org
Two subunits of the IL-12 receptor (IL-12R), IL-12Rβ1 and IL-12Rβ2, have been identified
and cloned. Previous studies demonstrated that the IL-12Rβ1 subunit was required for
mouse T and NK cells to respond to IL-12 in vivo. To investigate the role of IL-12Rβ2 in IL-12
signaling, we have generated IL-12Rβ2-deficient (IL-12Rβ2−/−) mice by targeted mutation in
embryonic stem (ES) cells. Although Con A-activated splenocytes from IL-12Rβ2−/− mice
still bind IL-12 with both high and low affinity, no IL-12-induced biological functions can be …
Abstract
Two subunits of the IL-12 receptor (IL-12R), IL-12Rβ1 and IL-12Rβ2, have been identified and cloned. Previous studies demonstrated that the IL-12Rβ1 subunit was required for mouse T and NK cells to respond to IL-12 in vivo. To investigate the role of IL-12Rβ2 in IL-12 signaling, we have generated IL-12Rβ2-deficient (IL-12Rβ2−/−) mice by targeted mutation in embryonic stem (ES) cells. Although Con A-activated splenocytes from IL-12Rβ2−/− mice still bind IL-12 with both high and low affinity, no IL-12-induced biological functions can be detected. Con A-activated splenocytes of IL-12Rβ2−/− mice failed to produce IFN-γ or proliferate in response to IL-12 stimulation. NK lytic activity of IL-12Rβ2−/− splenocytes was not induced when incubated with IL-12. IL-12Rβ2−/− splenocytes were deficient in IFN-γ secretion when stimulated with either Con A or anti-CD3 mAb in vitro. Furthermore, IL-12Rβ2−/− mice were deficient in vivo in their ability to produce IFN-γ following endotoxin administration and to generate a type 1 cytokine response. IL-12-mediated signal transduction was also defective as measured by phosphorylation of STAT4. These results demonstrate that although mouse IL-12Rβ1 is the subunit primarily responsible for binding IL-12, IL-12Rβ2 plays an essential role in mediating the biological functions of IL-12 in mice.
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