TLR ligands act directly upon T cells to restore proliferation in the absence of protein kinase C-θ signaling and promote autoimmune myocarditis

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-α-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-x_L, 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.