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J Immunol ; 177(3): 1886-93, 2006 Aug 01.
Article in English | MEDLINE | ID: mdl-16849501

ABSTRACT

T cell effector functions contribute to the pathogenesis of rheumatoid arthritis. PKC-theta transduces the signal from the TCR through activation of transcription factors NF-kappaB, AP-1, and NFAT. We examined the effects of PKC-theta deficiency on two Th1-dependent models of Ag-induced arthritis and found that PKC-theta-deficient mice develop disease, but at a significantly diminished severity compared with wild-type mice. In the methylated BSA model, cellular infiltrates and articular cartilage damage were mild in the PKC-theta-deficient mice as compared with wild-type mice. Quantitation of histopathology reveals 63 and 77% reduction in overall joint destruction in two independent experiments. In the type II collagen-induced arthritis model, we observed a significant reduction in clinical scores (p < 0.01) in three independent experiments and diminished joint pathology (p < 0.005) in PKC-theta-deficient compared with wild-type littermates. Microcomputerized tomographic imaging revealed that PKC-theta deficiency also protects from bone destruction. PKC-theta-deficient CD4(+) T cells show an impaired proliferative response, decreased intracellular levels of the cytokines IFN-gamma, IL-2, and IL-4, and significantly diminished cell surface expression of the activation markers CD25, CD69, and CD134/OX40 on memory T cells. We demonstrate decreased T-bet expression and significantly reduced IgG1 and IgG2a anti-collagen II Ab levels in PKC-theta-deficient mice. Collectively, our results demonstrate that PKC-theta deficiency results in an attenuated response to Ag-induced arthritis, which is likely mediated by the reduced T cell proliferation, Th1/Th2 cell differentiation and T cell activation before and during disease peak.


Subject(s)
Antigens/administration & dosage , Arthritis, Experimental/immunology , Arthritis, Experimental/prevention & control , Isoenzymes/deficiency , Isoenzymes/genetics , Protein Kinase C/deficiency , Protein Kinase C/genetics , Serum Albumin, Bovine/administration & dosage , Th1 Cells/immunology , Animals , Antigens/immunology , Arthritis, Experimental/enzymology , Arthritis, Experimental/genetics , Autoantibodies/biosynthesis , Autoantibodies/blood , Cell Movement/genetics , Cell Movement/immunology , Cell Proliferation , Collagen/administration & dosage , Collagen/immunology , Down-Regulation/genetics , Down-Regulation/immunology , Female , Immunophenotyping , Isoenzymes/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Knockout , Protein Kinase C/physiology , Protein Kinase C-theta , Serum Albumin, Bovine/immunology , T-Box Domain Proteins , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Th1 Cells/pathology , Transcription Factors/biosynthesis , Up-Regulation/immunology
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