title: TLR ligand induced IL-6 counter-regulates the anti-viral CD8(+) T cell response during an acute retrovirus infection.
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.
authors.affiliation: Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Weimin
authors.initials: W
authors.lastname: Wu
authors.affiliation: Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Kirsten K
authors.initials: KK
authors.lastname: Dietze
authors.affiliation: Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Gibbert
authors.affiliation: Institute for Immunology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Karl S
authors.initials: KS
authors.lastname: Lang
authors.affiliation: Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Trilling
authors.affiliation: Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Dongliang
authors.initials: D
authors.lastname: Yang
authors.affiliation: Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Mengji
authors.initials: M
authors.lastname: Lu
authors.affiliation: Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Roggendorf
authors.affiliation: Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Dittmer
authors.affiliation: 1] Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany [2] Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
mesh_terms: D000208:Acute Disease; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D005622:Friend murine leukemia virus / Q000472:pathogenicity* / Q000502:physiology; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D012192:Retroviridae Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000819:agonists* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014779:Virus Replication
chemical_list: D015850:Interleukin-6; D011948:Receptors, Antigen, T-Cell; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051193:Toll-Like Receptors; D007371:Interferon-gamma