TLR ligand induced IL-6 counter-regulates the anti-viral CD8+ T cell response during an acute retrovirus infection
Open Access
- 21 May 2015
- journal article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 5 (1), 10501
- https://doi.org/10.1038/srep10501
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.This publication has 62 references indexed in Scilit:
- When Toll-like receptor and T-cell receptor signals collide: a mechanism for enhanced CD8 T-cell effector functionBlood, 2010
- IL-17 and Th17 CellsAnnual Review of Immunology, 2009
- Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infectionThe Journal of Experimental Medicine, 2009
- The effects of IL-6 on CD4 T cell responsesClinical Immunology, 2008
- Identification of a distant T-bet enhancer responsive to IL-12/Stat4 and IFNγ/Stat1 signalsBlood, 2007
- Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cellsNature, 2006
- Pathogen Recognition and Innate ImmunityCell, 2006
- Toll-like receptor control of the adaptive immune responsesNature Immunology, 2004
- Toll-like receptor signallingNature Reviews Immunology, 2004
- IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses.JCI Insight, 1998