Regulation of the IL-12 receptor beta2 subunit by soluble antigen and IL-12 in vivo.
Continuous administration of soluble protein antigen to BALB/c mice inhibits the development of Th1 and induces selective differentiation of Th2 cells. Here we show that interleukin (IL)-12, administered together with soluble protein through a mini-osmotic pump implanted subcutaneously, not only prevents the inhibition of Th1 cell development, but stimulates higher interferon (IFN)-gamma production than in mice receiving IL-12 alone. In parallel to co-stimulation of Th1 cell development, co-administration of IL-12 blocks the Th2 response induced by soluble protein. IL-12 administered in adjuvant with antigen or intraperitoneally 2 days after the immunization does not break the inhibition of Th1 but can still decrease the Th2 response induced by pretreatment with soluble protein antigen. In contrast to IL-12, co-administration of IL-2 or IFN-gamma does not affect the diversion to Th2 induced by soluble antigen. Thus IL-12, but not IL-2 nor IFN-gamma, converts in vivo the inhibitory signal for Th1 cell development delivered by soluble antigen into an immunogenic one, while blocking a positive signal for Th2 cell differentiation. A molecular basis for the co-stimulation of Th1 priming and the prevention of Th2 differentiation by IL-12 in vivo is provided by the observation that transcripts encoding the IL-12 receptor beta2 chain, which is required for IL-12 signaling and Th1 cell development, are selectively inhibited by soluble antigen but are enhanced by IL-12 co-administration.
Galbiati
F
F
Roche Milano Ricerche, Italy.
Rogge
L
L
Guéry
J C
JC
Smiroldo
S
S
Adorini
L
L
D000818:Animals; D000941:Antigens / Q000276:immunology*; D002454:Cell Differentiation; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D007114:Immunization; D015918:Infusion Pumps, Implantable; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000008:administration & dosage / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009113:Muramidase / Q000276:immunology*; D010047:Ovalbumin / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000235:genetics; D053707:Receptors, Interleukin-12; D012995:Solubility; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D000941:Antigens; C508443:Il12rb2 protein, mouse; D007376:Interleukin-2; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D010047:Ovalbumin; D009113:Muramidase