PKC-θ-Deficient Mice Are Protected from Th1-Dependent Antigen-Induced Arthritis

Abstract

T cell effector functions contribute to the pathogenesis of rheumatoid arthritis. PKC-θ transduces the signal from the TCR through activation of transcription factors NF-κB, AP-1, and NFAT. We examined the effects of PKC-θ deficiency on two Th1-dependent models of Ag-induced arthritis and found that PKC-θ-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-θ-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-θ-deficient compared with wild-type littermates. Microcomputerized tomographic imaging revealed that PKC-θ deficiency also protects from bone destruction. PKC-θ-deficient CD4+ T cells show an impaired proliferative response, decreased intracellular levels of the cytokines IFN-γ, 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-θ-deficient mice. Collectively, our results demonstrate that PKC-θ 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.