Role of costimulation in the induction of the IL-12/IL-12 receptor pathway and the development of autoimmunity.
Costimulation mediated by the interactions of the B7 Ags (CD80/CD86) on APC with CD28 on the responding T cell regulates the magnitude of the immune response and may influence Th1/Th2 development. The IL-12Rbeta2 subunit plays a critical role in maintaining IL-12 responsiveness and controlling Th1 lineage commitment. We demonstrate that IL-2 and IL-12 resulting from CD28/B7 interactions both play a critical role in the induction of expression of the IL-12Rbeta2 subunit and as a result the differentiation of pathogenic autoreactive effector cells. These findings suggest that targeting IL-2 and IL-12 simultaneously may be effective in the treatment of Th1-mediated autoimmunity.
Chang
J T
JT
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
Segal
B M
BM
Shevach
E M
EM
D000069594:Abatacept; D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology; D018122:B7-1 Antigen / Q000502:physiology*; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand; D060908:CTLA-4 Antigen; D002454:Cell Differentiation / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology*; D018796:Immunoconjugates; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000494:pharmacology / Q000502:physiology; D007376:Interleukin-2 / Q000502:physiology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000502:physiology; D053707:Receptors, Interleukin-12; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007376:Interleukin-2; D008024:Ligands; D008562:Membrane Glycoproteins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D023201:CD40 Ligand; D018664:Interleukin-12; D000069594:Abatacept; D007371:Interferon-gamma