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

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.