IL-12 receptor beta 2 (IL-12R beta 2)-deficient mice are defective in IL-12-mediated signaling despite the presence of high affinity IL-12 binding sites
Cy. Wu et al., IL-12 receptor beta 2 (IL-12R beta 2)-deficient mice are defective in IL-12-mediated signaling despite the presence of high affinity IL-12 binding sites, J IMMUNOL, 165(11), 2000, pp. 6221-6228
Two subunits of the IL-12 receptor (IL-12R), IL-12R beta1 and IL-12R beta2,
have been identified and cloned. Previous studied dem demonstrated that th
e IL-12R beta1 subunit was required for mouse T and NK cells to respond to
IL-12 in vivo. To investigate the role of IL-12R beta2 in IL-12 signaling,
we have generated IL-12R beta2-deficient (IL-12R beta2(-/-)) mice by target
ed mutation in embryonic stem (ES) cells, Although Con A-activated splenocy
tes from IL-12R beta2(-/-) mice still bind IL-12 with both high and low aff
inity, no IL-12-induced biological functions can be detected, Con A-activat
ed splenocytes of IL-12R beta2(-/-) mice failed to produce IFN-gamma or pro
liferate in response to IL-12 stimulation. NK lytic activity of IL-12R beta
2(-/-) splenocytes was not induced when incubated with IL-12, IL-12R beta2(
-/-) splenocytes were deficient in IFN-gamma secretion when stimulated with
either Con A or anti-CD3 mAb in vitro, Furthermore, IL-12R beta2(-/-) mice
were deficient in vivo in their ability to produce IFN-gamma following end
otoxin administration and to generate a type I cytokine response, IL-12-med
iated signal transduction was also defective as measured by phosphorylation
of STAT4, These results demonstrate that although mouse IL-12R beta1 is th
e subunit primarily responsible for binding IL-12, IL-12R beta2 plays an es
sential role in mediating the biological functions of IL-12 in mice.