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More MS news articles for October 2003

Role of IL-12 Receptor beta1 in Regulation of T Cell Response by APC in Experimental Autoimmune Encephalomyelitis

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14568921&dopt=Abstract

J Immunol. 2003 Nov 1;171(9):4485-92
Zhang GX, Yu S, Gran B, Li J, Siglienti I, Chen X, Calida D, Ventura E, Kamoun M, Rostami A.
Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107. Pathology and Laboratory Medicine and 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-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.