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-Deficient Mice
Lilly Research Laboratories, Eli Lilly, Indianapolis, IN 46285
The protein kinase C
(PKC) 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 on T cell function in inflammatory autoimmune disease have not been thoroughly examined. In this study we used PKC-deficient mice to investigate the potential involvement of PKC in the development of experimental autoimmune encephalomyelitis, a prototypic T cell-mediated autoimmune disease model of the CNS. We found that PKC–/– 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–/– mice revealed significantly reduced production of the Th1 cytokine IFN-
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–/– mice compared with wild-type mice during the disease course. In addition, PKC–/– 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–/– mice as well as in in vitro-stimulated CD4+ T cells compared with wild-type mice. These results underscore the importance of PKC in the regulation of multiple T cell functions necessary for the development of autoimmune disease.
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