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

Benjamin J. Marsland, Chiara Nembrini, Katja Grün, Regina Reissmann, Michael Kurrer, Carola Leipner, Manfred Kopf

Research output: Contribution to journalArticleResearchpeer-review

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-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-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.

Original languageEnglish
Pages (from-to)3466-3473
Number of pages8
JournalJournal of Immunology
Volume178
Issue number6
Publication statusPublished - 15 Mar 2007
Externally publishedYes

Cite this

Marsland, Benjamin J. ; Nembrini, Chiara ; Grün, Katja ; Reissmann, Regina ; Kurrer, Michael ; Leipner, Carola ; Kopf, Manfred. / TLR ligands act directly upon T cells to restore proliferation in the absence of protein kinase C-θ signaling and promote autoimmune myocarditis. In: Journal of Immunology. 2007 ; Vol. 178, No. 6. pp. 3466-3473.
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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-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-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.",
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TLR ligands act directly upon T cells to restore proliferation in the absence of protein kinase C-θ signaling and promote autoimmune myocarditis. / Marsland, Benjamin J.; Nembrini, Chiara; Grün, Katja; Reissmann, Regina; Kurrer, Michael; Leipner, Carola; Kopf, Manfred.

In: Journal of Immunology, Vol. 178, No. 6, 15.03.2007, p. 3466-3473.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - TLR ligands act directly upon T cells to restore proliferation in the absence of protein kinase C-θ signaling and promote autoimmune myocarditis

AU - Marsland, Benjamin J.

AU - Nembrini, Chiara

AU - Grün, Katja

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AU - Kurrer, Michael

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AU - Kopf, Manfred

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