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.
Two subunits of the IL-12 receptor (IL-12R), IL-12R beta 1 and IL-12R beta 2, have been identified and cloned. Previous studies demonstrated that the IL-12R beta 1 subunit was required for mouse T and NK cells to respond to IL-12 in vivo. To investigate the role of IL-12R beta 2 in IL-12 signaling, we have generated IL-12R beta 2-deficient (IL-12R beta 2(-/-)) mice by targeted mutation in embryonic stem (ES) cells. Although Con A-activated splenocytes from IL-12R beta 2(-/-) 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-12R beta 2(-/-) mice failed to produce IFN-gamma or proliferate 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 beta 2(-/-) splenocytes were deficient in IFN-gamma secretion when stimulated with either Con A or anti-CD3 mAb in vitro. Furthermore, IL-12R beta 2(-/-) mice were deficient in vivo in their ability to produce IFN-gamma 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-12R beta 1 is the subunit primarily responsible for binding IL-12, IL-12R beta 2 plays an essential role in mediating the biological functions of IL-12 in mice.
Wu
C
C
Department of Inflammation/Autoimmune Diseases, Hoffmann-LaRoche, Nutley, NJ 07110, USA.
Wang
X
X
Gadina
M
M
O'Shea
J J
JJ
Presky
D H
DH
Magram
J
J
D000818:Animals; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D003208:Concanavalin A / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D018390:Gene Targeting; D007108:Immune Tolerance / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D010766:Phosphorylation; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018123:Receptors, Interleukin / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D003208:Concanavalin A; D018664:Interleukin-12; D007371:Interferon-gamma