Characterization of IL-12 receptor beta1 chain (IL-12Rbeta1)-deficient mice: IL-12Rbeta1 is an essential component of the functional mouse IL-12 receptor.
Two chains of the IL-12R, IL-12Rbeta1 and IL-12Rbeta2, have recently been cloned. To determine the role of IL-12Rbeta1 in mediating the biologic functions of IL-12 in mice, we have generated IL-12Rbeta1-deficient (IL-12Rbeta1(-/-)) mice by targeted mutation in ES cells. Con A-activated splenocytes from IL-12Rbeta1(+/+) mice displayed both high and low affinity IL-12-binding sites, whereas Con A-activated splenocytes from IL-12Rbeta1(-/-) mice expressed only low affinity IL-12-binding sites. Consistent with the expression of low affinity IL-12-binding sites on IL-12Rbeta1(-/-) lymphoblasts, these cells expressed normal amounts of IL-12Rbeta2 mRNA. Unlike those from IL-12Rbeta1(+/+) mice, Con A-activated splenocytes from IL-12Rbeta1(-/-) 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-12Rbeta1(-/-) 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-12Rbeta1(-/-) mice were impaired in their ability to produce IFN-gamma in response to endotoxin administration in vivo, and IL-12Rbeta1(-/-) 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-12Rbeta1 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-12Rbeta2, is by itself insufficient to mediate IL-12 responsiveness, even in the presence of very high concentrations of IL-12.
Wu
C
C
Department of Inflammation/Autoimmune Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.
Ferrante
J
J
Gately
M K
MK
Magram
J
J
D000818:Animals; D001665:Binding Sites; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D018123:Receptors, Interleukin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D053707:Receptors, Interleukin-12
C508440:Il12rb1 protein, mouse; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D007371:Interferon-gamma