TLR Ligands Act Directly upon T Cells to Restore Proliferation in the Absence of Protein Kinase C-θ Signaling and Promote Autoimmune Myocarditis

Abstract

The serine/threonine kinase, protein kinase C-θ (PKC-θ), plays a central role in the activation and differentiation of Th2 cells while being redundant in CD4+ and CD8+ antiviral responses. Recent evidence indicates that PKC-θ may however be required for some T cell-driven autoimmune responses. We have investigated the role of PKC-θ in the induction of autoimmune myocarditis induced by either Coxsackie B3 virus infection or immunization with α-myosin/CFA (experimental autoimmune myocarditis (EAM)). PKC-θ-deficient mice did not develop EAM as shown by impaired inflammatory cell infiltration into the heart, reduced CD4+ T cell IL-17 production, and the absence of a myosin-specific Ab response. Comparatively, PKC-θ was not essential for both early and late-phase Coxsackie virus-induced myocarditis. We sought to find alternate pathways of immune stimulation that might reconcile the differential requirements for PKC-θ in these two disease models. We found systemic administration of the TLR ligand CpG restored EAM in PKC-θ-deficient mice. CpG could act directly upon TLR9-expressing T cells to restore proliferation and up-regulation of Bcl-xL, but exogenous IL-6 and TGF-β was required for Th17 cell differentiation. Taken together, these results indicate that TLR-mediated activation of T cells can directly overcome the requirement for PKC-θ signaling and, combined with the dendritic cell-derived cytokine milieu, can promote the development of autoimmunity.

TLR2 Engagement on CD8 T Cells Enables Generation of Functional Memory Cells in Response to a Suboptimal TCR Signal

“…We have also shown for the first time that TCR and TLR2 signals cooperate in vivo to induce naive CD8 T cell proliferation and expansion in response to altered peptide ligands. Together with the recent report of Marsland et al (30) demonstrating that TLR9 engagement in CD4 T cells is sufficient to restore proliferation of anergic protein kinase C--deficient T cells, our results indicate that the threshold for TCR-mediated signaling can be directly modulated by TLR2 and TLR9 engagement in T cells. At a molecular level, we have shown in this study that TLR2 engagement on CD8 T cells increases PKB phosphorylation induced after TCR stimulation with low doses of peptide or with altered peptide ligands.…”

“…associated with an infection by Borrelia burgdorferi, that the outer surface protein A of this bacterium stimulates TLR2 and could directly trigger the release of proinflammatory cytokines from effector T cells (20). Evidence for a direct role of TLR on effector T cells in the development of autoimmune diseases has also been recently suggested in a model of experimental autoimmune myocarditis induced by immunizing protein kinase C--deficient mice with myosin peptide in CFA (30). In those mice, systemic administration of CpG in addition to immunization with myosin H chain peptide is required to develop an autoimmune myocarditis.…”

TLR-dependent T cell activation in autoimmunity

“…Moreover, stimulation with CpG restored the proliferation of highly purified naïve T cells from Pkcθ -/-mice in response to CD3-specific antibody stimulation 90 .…”

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

“…16 Further, TLR9 ligand CpG was recently shown to directly act on T-cell proliferation and survival, bypassing the PKC-pathway. 17 Therefore, the implication of PKC-in the T-cell pathway during development of experimental CM remains to be established.…”