Role of IL-12 receptor beta 1 in regulation of T cell response by APC in experimental autoimmune encephalomyelitis.
IL-12 was thought to be involved in the development of experimental autoimmune encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disorder of the CNS. However, we have recently found that IL-12 responsiveness, via IL-12Rbeta2, is not required in the induction of EAE. To determine the role of IL-12Rbeta1, a key subunit for the responsiveness to both IL-12 and IL-23, in the development of autoimmune diseases, we studied EAE in mice deficient in this subunit of IL-12R. IL-12Rbeta1(-/-) mice are completely resistant to myelin oligodendrocyte glycoprotein (MOG)-induced EAE, with an autoantigen-specific Th2 response. To study the mechanism underlying this Th2 bias, we cocultured purified CD4(+) T cells and APCs of MOG-immunized mice. We demonstrate that IL-12Rbeta1(-/-) APCs drive CD4(+) T cells of both wild-type and IL-12Rbeta1(-/-) mice to an Ag-induced Th2 phenotype, whereas wild-type APCs drive these CD4(+) T cells toward a Th1 type. IL-12Rbeta1(-/-) CD4(+) T cells, in turn, appear to exert an immunoregulatory effect on the capacity of wild-type APCs to produce IFN-gamma and TNF-alpha. Furthermore, decreased levels of IL-12p40, p35, and IL-23p19 mRNA expression were found in IL-12Rbeta1(-/-) APCs, indicating an autocrine pathway of IL-12/IL-23 via IL-12Rbeta1. IL-18 production and IL-18Ralpha expression are also significantly decreased in IL-12Rbeta1(-/-) mice immunized with MOG. We conclude that in the absence of IL-12Rbeta1, APCs play a prominent regulatory role in the induction of autoantigen-specific Th2 cells.
Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107-5083, USA.
Guang-Xian
GX
Zhang
Shuo
S
Yu
Bruno
B
Gran
Jifen
J
Li
Ines
I
Siglienti
Xiaohan
X
Chen
Divina
D
Calida
Elvira
E
Ventura
Malek
M
Kamoun
Abdolmohamad
A
Rostami
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D053765:Interleukin-12 Subunit p35; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000276:immunology; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053707:Receptors, Interleukin-12; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology
D006023:Glycoproteins; C508841:Il23a protein, mouse; D053765:Interleukin-12 Subunit p35; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D021122:Protein Subunits; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; C445081:myelin oligodendrocyte glycoprotein (35-55); D018664:Interleukin-12