Journal
JOURNAL OF IMMUNOLOGY
Volume 176, Issue 5, Pages 2872-2879Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.176.5.2872
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The protein kinase CO (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 MOG(35)-(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 MOG(35-55) 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 MOG(35-55)-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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