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Neutralization of IL-10 produced by B cells promotes protective immunity during persistent HCV infection in humanized mice |
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| Authors: | Min Liu Han-Yu Chen Liang Luo Yaping Wang Dongli Zhang Neng Song Fu-Bing Wang Qiao Li Xiao-Lian Zhang Qin Pan |
| Institution: | 1. Department of Immunology, Hubei Province Key Laboratory of Allergy and Immunology, State Key Laboratory of Virology and Medical Research Institute, Wuhan University School of Basic Medical Sciences, Wuhan, China
Liu, Chen, and Luo contributed equally to this work.;2. Department of Immunology, Hubei Province Key Laboratory of Allergy and Immunology, State Key Laboratory of Virology and Medical Research Institute, Wuhan University School of Basic Medical Sciences, Wuhan, China Department of Laboratory Medicine, Jingzhou Central Hospital, Jingzhou, Hubei Province, China Liu, Chen, and Luo contributed equally to this work.;3. Department of Immunology, Hubei Province Key Laboratory of Allergy and Immunology, State Key Laboratory of Virology and Medical Research Institute, Wuhan University School of Basic Medical Sciences, Wuhan, China;4. Department of Laboratory Medicine, Hubei Provincial Hospital of Integrated Chinese & Western Medicine, Wuhan, China;5. Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China;6. Department of Surgery, University of Michigan, Ann Arbor, MI, USA |
| Abstract: | Chronic HCV infection can lead to cirrhosis and is associated with increased mortality. Interleukin (IL)-10-producing B cells (B10 cells) are regulatory cells that suppress cellular immune responses. Here, we aimed to determine whether HCV induces B10 cells and assess the roles of the B10 cells during HCV infection. HCV-induced B10 cells were enriched in CD19hi and CD1dhiCD5+ cell populations. HCV predominantly triggered the TLR2-MyD88-NF-κB and AP-1 signaling pathways to drive IL-10 production by B cells. In a humanized murine model of persistent HCV infection, to neutralize IL-10 produced by B10 cells, mice were treated with pcCD19scFv-IL-10R, which contains the genes coding the anti-CD19 single-chain variable fragment (CD19scFv) and the extracellular domain of IL-10 receptor alpha chain (sIL-10Ra). This treatment resulted in significant reduction of B10 cells in spleen and liver, increase of cytotoxic CD8+ T-cell responses against HCV, and low viral loads in infected humanized mice. Our results indicate that targeting B10 cells via neutralization of IL-10 may offer a novel strategy to enhance anti-HCV immunotherapy. |
| Keywords: | B cells HCV IL-10 Immunotherapy Infection |