CHARACTERIZATION OF IL-12 RECEPTOR BETA-1 CHAIN (IL-12R-BETA-1)-DEFICIENT MICE - IL-12R-BETA-1 IS AN ESSENTIAL COMPONENT OF THE FUNCTIONAL-MOUSE IL-12 RECEPTOR

Two chains of the IL-12R, IL-12R beta 1 and IL-12R beta 2, have recent ly been cloned, To determine the role of IL-12R beta 1 in mediating th e biologic functions of IL-12 in mice, we have generated IL-12R beta 1 -deficient (IL-12R beta 1(-/-)) mice by targeted mutation in ES cells, Con A-activated splenocytes from IL-12R beta 1(+/+) mice displayed bo th high and low affinity IL-12-binding sites, whereas Con A-activated splenocytes from IL-12R beta 1(-/-) mice expressed only low affinity I L-12-binding sites, Consistent with the expression of low affinity IL- 12-binding sites on IL-12R beta 1(-/-) lymphoblasts, these cells expre ssed normal amounts of IL-12R beta 2 mRNA. Unlike those from IL-12R be ta 1(+/+) mice, Con A-activated splenocytes from IL-12R beta 1(-/-) mi ce failed to proliferate or produce IFN-gamma in response to IL-12, ev en at very high concentrations (67 nM). In contrast, lymphoblasts from both types of mice proliferated equally well to IL-2 or IL-7. Splenoc ytes from IL-12R beta 1(-/-) mice also failed to display enhanced NK l ytic activity when cultured with IL-12 but responded normally to IL-2, Similar to IL-12 p40-deficient mice, IL-12R beta 1(-/-) mice were imp aired in their ability to produce IFN-gamma in response to endotoxin a dministration in vivo, and IL-12R beta 1(-/-) splenocytes were deficie nt in IFN-gamma secretion when stimulated with either Con A or soluble anti-CD3 mAb in vitro, These results demonstrate that IL-12R beta 1 i s required for mouse T and NK cells to respond to IL-12 and that expre ssion of low affinity IL-12-binding sites, presumably reflecting expre ssion of IL-12R beta 2, is by itself insufficient to mediate IL-12 res ponsiveness, even in the presence of very high concentrations of IL-12 .