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 recently been cloned, To determine the role of IL-12R beta 1 in mediating the 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 both high and low affinity IL-12-binding sites, whereas Con A-activated splenocytes from IL-12R beta 1(-/-) mice expressed only low affinity IL-12-binding sites, Consistent with the expression of low affinity IL-12-binding sites on IL-12R beta 1(-/-) lymphoblasts, these cells expressed normal amounts of IL-12R beta 2 mRNA. Unlike those from IL-12R beta 1(+/+) mice, Con A-activated splenocytes from IL-12R beta 1(-/-) mice failed to proliferate or produce IFN-gamma in response to IL-12, even at very high concentrations (67 nM). In contrast, lymphoblasts from both types of mice proliferated equally well to IL-2 or IL-7. Splenocytes from IL-12R beta 1(-/-) mice also failed to display enhanced NK lytic 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 impaired in their ability to produce IFN-gamma in response to endotoxin administration in vivo, and IL-12R beta 1(-/-) splenocytes were deficient 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 is required for mouse T and NK cells to respond to IL-12 and that expression of low affinity IL-12-binding sites, presumably reflecting expression of IL-12R beta 2, is by itself insufficient to mediate IL-12 responsiveness, even in the presence of very high concentrations of IL-12.