title: Kupffer Cells Support Hepatitis B Virus-Mediated CD8+ T Cell Exhaustion via Hepatitis B Core Antigen-TLR2 Interactions in Mice.
abstract: Hepatitis B virus (HBV) persistence is a fundamental process in chronic HBV infection and a key factor in all related liver diseases; however, the mechanisms have yet to be elucidated. We studied the role of TLR2 in HBV persistence using a well-established HBV-carrier mouse model generated by hydrodynamically injecting a phospho-adeno-associated virus/HBV1.2 plasmid into mice. We found that a genetic deficiency in TLR2 improves HBV elimination, whereas activating TLR2 led to more stable HBV persistence, suggesting that TLR2 activation is critical in HBV persistence. Furthermore, we noted that TLR2 activation could inhibit CD8(+) T cell function, causing the exhaustion phenotype in HBV-carrier mice, because TLR2 deficiency might rescue CD8(+) T cell function in a cellular adoptive experiment. TLR2 expression on Kupffer cells (KCs) was upregulated in HBV-carrier mice, which accounts for HBV persistence, because the difference in anti-HBV immunity between HBV-carrier wild-type and Tlr2(-/-) mice did not exist after KC depletion. In addition, similar to TLR2 deficiency, after KC depletion, CD8(+) T cells were more efficiently activated in HBV-carrier mice, leading to rapid HBV elimination. KCs produced more IL-10 upon TLR2 activation in response to direct hepatitis B core Ag stimulation, and the elevated IL-10 inhibited CD8(+) T cell function in HBV-carrier mice, because IL-10 deficiency or anti-IL-10R treatment resulted in CD8(+) T cells with stronger antiviral function. In conclusion, KCs support liver tolerance by inducing anti-HBV CD8(+) T cell exhaustion via IL-10 production after TLR2 activation by hepatitis B core Ag stimulation.
authors: Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China;
authors: Min
authors: M
authors: Li
authors: Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China; and Institute of Immunology and Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Rui
authors: R
authors: Sun
authors: Institute of Immunology and Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Long
authors: L
authors: Xu
authors: Institute of Immunology and Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Wenwei
authors: W
authors: Yin
authors: Institute of Immunology and Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Yongyan
authors: Y
authors: Chen
authors: Institute of Immunology and Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Xiaodong
authors: X
authors: Zheng
authors: Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China; Institute of Immunology and Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Zhexiong
authors: Z
authors: Lian
authors: Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China; Institute of Immunology and Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Haiming
authors: H
authors: Wei
authors: Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China; and Institute of Immunology and Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China tzg@ustc.edu.cn.
authors: Zhigang
authors: Z
authors: Tian
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002353:Carrier State / Q000276:immunology* / Q000821:virology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000235:genetics; D006512:Hepatitis B Core Antigens / Q000276:immunology*; D006515:Hepatitis B virus / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000821:virology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology*; D007728:Kupffer Cells / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053701:Receptors, Interleukin-10 / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*
chemical_list: D006512:Hepatitis B Core Antigens; C556062:IL10 protein, mouse; D053701:Receptors, Interleukin-10; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D016753:Interleukin-10