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The Journal of Immunology, 2003, 171: 4485-4492.
Copyright © 2003 by The American Association of Immunologists

Role of IL-12 Receptor {beta}1 in Regulation of T Cell Response by APC in Experimental Autoimmune Encephalomyelitis 1

Guang-Xian Zhang*, Shuo Yu*, Bruno Gran*, Jifen Li{dagger}, Ines Siglienti*, Xiaohan Chen{ddagger}, Divina Calida*, Elvira Ventura*, Malek Kamoun{dagger} and Abdolmohamad Rostami2,*

* Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107; and Departments of {dagger} Pathology and Laboratory Medicine and {ddagger} Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

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-/- 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-12R{beta}1-/- APCs drive CD4+ T cells of both wild-type and IL-12R{beta}1-/- mice to an Ag-induced Th2 phenotype, whereas wild-type APCs drive these CD4+ T cells toward a Th1 type. IL-12R{beta}1-/- 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-12R{beta}1-/- 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-/- 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.




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