Wu Weimin, Dietze Kirsten K, Gibbert Kathrin, Lang Karl S, Trilling Mirko, Yan Huimin, Wu Jun, Yang Dongliang, Lu Mengji, Roggendorf Michael, Dittmer Ulf, Liu Jia
Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
Institute for Immunology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
Sci Rep. 2015 May 21;5:10501. doi: 10.1038/srep10501.
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.
我们之前已经表明，Toll样受体（TLR）激动剂通过增强病毒特异性CD8(+) T细胞反应，有助于控制病毒感染。同样众所周知的是，TLR信号传导会导致促炎细胞因子如白细胞介素6（IL-6）的产生。然而，在TLR激动剂刺激过程中，这些促炎细胞因子如何影响病毒特异性CD8(+) T细胞反应，在很大程度上仍不清楚。在此，我们在Friend逆转录病毒（FV）小鼠模型中研究了TLR诱导的IL-6在塑造病毒特异性CD8(+) T细胞反应中的作用。我们发现，TLR激动剂诱导的IL-6对效应性CD8(+) T细胞反应具有反向调节作用。IL-6在体外强烈抑制CD8(+) T细胞的活化和细胞因子产生。这种效应是由IL-6对CD8(+) T细胞的直接刺激介导的，它诱导STAT3磷酸化和SOCS3上调，并下调STAT4磷酸化和T-bet。此外，在急性FV感染期间联合TLR刺激和IL-6阻断，可增强病毒特异性CD8(+) T细胞免疫，并更好地控制病毒复制。这些结果对于我们理解TLR诱导的促炎细胞因子在调节效应T细胞反应中的作用，以及对于开发克服慢性病毒感染中T细胞功能障碍的治疗策略具有重要意义。
