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- 12R[beta]2, is not required in the induction of EAE. To determine the role of...

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Published in:The Journal of immunology (1950) 2003-11, Vol.171 (9), p.4485-4492
Main Authors: Zhang, Guang-Xian, Yu, Shuo, Gran, Bruno, Li, Jifen, Siglienti, Ines, Chen, Xiaohan, Calida, Divina, Ventura, Elvira, Kamoun, Malek, Rostami, Abdolmohamad
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Language:English
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Summary: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- 12R[beta]2, is not required in the induction of EAE. To determine the role of IL-12R[beta]1, 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-12R[beta]1 super(-/-) 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 super(+) T cells and APCs of MOG-immunized mice. We demonstrate that IL-12R[beta]1 super(-/-) APCs drive CD4 super(+) T cells of both wild-type and IL- 12R[beta]1 super(-/-) mice to an Ag-induced Th2 phenotype, whereas wild-type APCs drive these CD4 super(+) T cells toward a Th1 type. IL-12R[beta]1 super(-/-) CD4 super(+) 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- 12R[beta]1 super(-/-) APCs, indicating an autocrine pathway of IL-12/IL-23 via IL- 12R[beta]1. IL-18 production and IL-18R[alpha] expression are also significantly decreased in IL-12R[beta]1 super(-/-) mice immunized with MOG. We conclude that in the absence of IL-12R[beta]1, APCs play a prominent regulatory role in the induction of autoantigen-specific Th2 cells.
ISSN:0022-1767
1550-6606