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

Weimin Wu, Kirsten K. Dietze, Kathrin Gibbert, Karl S. Lang, Mirko Trilling, Huimin Yan, Jun Wu, Dongliang Yang, Mengji Lu, Michael Roggendorf, Ulf Dittmer, Jia Liu

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

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.

Original languageEnglish
Article number10501
JournalScientific Reports
Volume5
DOIs
StatePublished - 21 May 2015
Externally publishedYes

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