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The Journal of Immunology, 2006, 176: 2872-2879.
Copyright © 2006 by The American Association of Immunologists

Resistance to Experimental Autoimmune Encephalomyelitis and Impaired IL-17 Production in Protein Kinase C{theta}-Deficient Mice

Seng-Lai Tan, Jingyong Zhao, Chen Bi, XinYi Cynthia Chen, Deena L. Hepburn, Jian Wang, Jonathon D. Sedgwick, Subba R. Chintalacharuvu1 and Songqing Na1

Lilly Research Laboratories, Eli Lilly, Indianapolis, IN 46285

The protein kinase C{theta} (PKC{theta}) serine/threonine kinase has been implicated in signaling of T cell activation, proliferation, and cytokine production. However, the in vivo consequences of ablation of PKC{theta} on T cell function in inflammatory autoimmune disease have not been thoroughly examined. In this study we used PKC{theta}-deficient mice to investigate the potential involvement of PKC{theta} in the development of experimental autoimmune encephalomyelitis, a prototypic T cell-mediated autoimmune disease model of the CNS. We found that PKC{theta}–/– mice immunized with the myelin oligodendrocyte glycoprotein (MOG) peptide MOG35–55 were completely resistant to the development of clinical experimental autoimmune encephalomyelitis compared with wild-type control mice. Flow cytometric and histopathological analysis of the CNS revealed profound reduction of both T cell and macrophage infiltration and demyelination. Ex vivo MOG35–55 stimulation of splenic T lymphocytes from immunized PKC{theta}–/– mice revealed significantly reduced production of the Th1 cytokine IFN-{gamma} as well as the T cell effector cytokine IL-17 despite comparable levels of IL-2 and IL-4 and similar cell proliferative responses. Furthermore, IL-17 expression was dramatically reduced in the CNS of PKC{theta}–/– mice compared with wild-type mice during the disease course. In addition, PKC{theta}–/– T cells failed to up-regulate LFA-1 expression in response to TCR activation, and LFA-1 expression was also significantly reduced in the spleens of MOG35–55-immunized PKC{theta}–/– mice as well as in in vitro-stimulated CD4+ T cells compared with wild-type mice. These results underscore the importance of PKC{theta} in the regulation of multiple T cell functions necessary for the development of autoimmune disease.




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