title: TLR ligands act directly upon T cells to restore proliferation in the absence of protein kinase C-theta signaling and promote autoimmune myocarditis.
abstract: 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.
authors.affiliation: Molecular Biomedicine, Swiss Federal Institute of Technology, Wagistrasse 27, CH 8952 Zurich-Schlieren, Switzerland. marsland@env.ethz.ca
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Marsland
authors.forename: Chiara
authors.initials: C
authors.lastname: Nembrini
authors.forename: Katja
authors.initials: K
authors.lastname: Grün
authors.forename: Regina
authors.initials: R
authors.lastname: Reissmann
authors.forename: Michael
authors.initials: M
authors.lastname: Kurrer
authors.forename: Carola
authors.initials: C
authors.lastname: Leipner
authors.forename: Manfred
authors.initials: M
authors.lastname: Kopf
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D003384:Coxsackievirus Infections / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D018899:CpG Islands / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D029822:Enterovirus B, Human / Q000276:immunology; D007527:Isoenzymes / Q000172:deficiency* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009205:Myocarditis / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000821:virology; D009206:Myocardium / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D010455:Peptides / Q000276:immunology / Q000633:toxicity; D011493:Protein Kinase C / Q000172:deficiency* / Q000276:immunology; D000074121:Protein Kinase C-theta; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D007527:Isoenzymes; D010455:Peptides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta