TLR ligand induced IL-6 counter-regulates the anti-viral CD8+ T cell response during an acute retrovirus infection

Wu, Weimin, Dr. rer. nat. Dietze, Kirsten, Dr. rer. nat. Gibbert, Kathrin, Prof. Dr. med. Lang, Karl Sebastian, Prof. Dr. rer. nat. Trilling, Mirko, Yan, Huimin, Wu, Jun, Yang, Dongliang, Prof. Dr. Lu, Mengji, Prof. Dr. med. Roggendorf, Michael, Univ.-Prof. Dr. rer. nat. Dittmer, Ulf, Liu, Jia

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We have previously shown that Toll-like receptor (TLR) agonists contribute to the control of viral infection by augmenting virus-specific CD8+ T-cell responses. It is also well established that signaling by TLRs results in the production of pro-inflammatory cytokines such as interleukin 6 (IL-6). However, how these pro-inflammatory cytokines influence the virus-specific CD8+ T-cell response during the TLR agonist stimulation remained largely unknown. Here, we investigated the role of TLR-induced IL-6 in shaping virus-specific CD8+ T-cell responses in the Friend retrovirus (FV) mouse model. We show that the TLR agonist induced IL-6 counter-regulates effector CD8+ T-cell responses. IL-6 potently inhibited activation and cytokine production of CD8+ T cells in vitro. This effect was mediated by a direct stimulation of CD8+ T cells by IL-6, which induced upregulation of STAT3 phosphorylation and SOCS3 and downregulated STAT4 phosphorylation and T-bet. Moreover, combining TLR stimulation and IL-6 blockade during an acute FV infection resulted in enhanced virus-specific CD8+ T-cell immunity and better control of viral replication. These results have implications for our understanding of the role of TLR induced pro-inflammatory cytokines in regulating effector T cell responses and for the development of therapeutic strategies to overcome T cell dysfunction in chronic viral infections.
PURL / DOI:
Lesezeichen:
Dokumententyp:
Wissenschaftliche Texte » Artikel, Aufsatz
Fakultät / Institut:
Medizinische Fakultät » Universitätsklinikum Essen » Institut für Virologie
Medizinische Fakultät » Universitätsklinikum Essen » Institut für Immunologie
Dewey Dezimal-Klassifikation:
600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit
Stichwörter:
Medical research
Sprache:
Englisch
Kollektion / Status:
E-Publikationen / Dokument veröffentlicht
Dateien geändert am:
26.01.2018
Medientyp:
Text
Lizenz:
Creative Commons Namensnennung 4.0 InternationalDieses Werk kann unter einer Creative Commons Namensnennung 4.0 International Lizenz genutzt werden.
Quelle:
Scientific Reports, 2015, 5:10501; published online: 21 May 2015