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TLR ligands act directly upon T cells to restore proliferation in the absence of protein kinase C-theta signaling and promote autoimmune myocarditis.
Journal of Immunology
The serine/threonine kinase, protein kinase C-theta (PKC-theta), 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-theta may however be required for some T cell-driven autoimmune responses. We have investigated the role of PKC-theta in the induction of autoimmune myocarditis induced by either Coxsackie B3 virus infection or immunization with alpha-myosin/CFA (experimental autoimmune myocarditis (EAM)). PKC-theta-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-theta 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-theta in these two disease models. We found systemic administration of the TLR ligand CpG restored EAM in PKC-theta-deficient mice. CpG could act directly upon TLR9-expressing T cells to restore proliferation and up-regulation of Bcl-x(L), but exogenous IL-6 and TGF-beta 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-theta signaling and, combined with the dendritic cell-derived cytokine milieu, can promote the development of autoimmunity.
Animals, Autoimmune Diseases/chemically induced, Autoimmune Diseases/enzymology, Autoimmune Diseases/</QualifierName> <QualifierName MajorTopicYN="N">, CD8-Positive T-Lymphocytes/enzymology, CD8-Positive T-Lymphocytes/immunology, Cell Differentiation/genetics, Cell Differentiation/immunology, Cell Proliferation, Coxsackievirus Infections/enzymology, Coxsackievirus Infections/immunology, CpG Islands/immunology, Cytokines/biosynthesis, Cytokines/immunology, Dendritic Cells/enzymology, Dendritic Cells/immunology, Enterovirus B, Human/immunology, Isoenzymes/deficiency, Isoenzymes/immunology, Mice, Mice, Inbred BALB C, Mice, Knockout, Myocarditis/chemically induced, Myocarditis/enzymology, Myocarditis/</QualifierName> <QualifierName MajorTopicYN="N">, Myocardium/enzymology, Myocardium/immunology, Peptides/immunology, Peptides/toxicity, Protein Kinase C/deficiency, Protein Kinase C/immunology, Signal Transduction/genetics, Signal Transduction/immunology, Th2 Cells/enzymology, Th2 Cells/immunology, Toll-Like Receptor 9/immunology, Toll-Like Receptor 9/metabolism
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