Resistance to experimental autoimmune encephalomyelitis and impaired IL-17 production in protein kinase C theta-deficient mice.
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 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.
Lilly Research Laboratories, Eli Lilly, Indianapolis, IN 46285, USA.
Seng-Lai
SL
Tan
Jingyong
J
Zhao
Chen
C
Bi
Xinyi Cynthia
XC
Chen
Deena L
DL
Hepburn
Jian
J
Wang
Jonathon D
JD
Sedgwick
Subba R
SR
Chintalacharuvu
Songqing
S
Na
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D004198:Disease Susceptibility; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D011493:Protein Kinase C / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D000074121:Protein Kinase C-theta; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D006023:Glycoproteins; D020381:Interleukin-17; D007527:Isoenzymes; D016169:Lymphocyte Function-Associated Antigen-1; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D007371:Interferon-gamma; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta