title: Blockade of Tim-3 signaling restores the virus-specific CD8⁺ T-cell response in patients with chronic hepatitis B.
abstract: Chronic hepatitis B (CHB) is characterized by functionally impaired virus-specific CD8(+)  T-cell responses. However, the mechanism underlying this dysfunction has not been fully clarified. We examined the role of a newly identified protein, T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3), in regulating the antiviral CD8(+)  T-cell response in CHB patients. Tim-3 expression on peripheral virus-specific CD8(+)  T cells from 20 CHB patients and 20 healthy controls was determined by flow cytometry. The phenotypes and cytokine-producing capacity were compared between Tim-3(+) CD8(+)  and Tim-3(-) CD8(+)  T cells. The impact of Tim-3 signaling on cellular proliferation and cytokine-producing capacity was also studied. Tim-3 expression on hepatitis B virus (HBV)-specific CD8(+)  T cells was higher than expression on cytomegalovirus (CMV)-specific CD8(+)  T cells. Tim-3(+)  CD8(+)  T cells exhibited proliferative senescence phenotypes and decreased cytokine production upon antigen challenge. Finally, blocking the Tim-3 pathway significantly improved proliferation and antiviral cytokine secretion of CD8(+)  T cells in response to HBV-specific antigen peptides. Tim-3 negatively regulates antiviral responses of CD8(+)  T cells isolated from CHB patients, and this response is reversed by blocking the Tim-3 pathway.
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.forename: Shuping
authors.initials: S
authors.lastname: Li
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yanning
authors.initials: Y
authors.lastname: Liu
authors.forename: Yihua
authors.initials: Y
authors.lastname: Wu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000328:Adult; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2; D019694:Hepatitis B, Chronic / Q000276:immunology*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D008875:Middle Aged; D010455:Peptides / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D016207:Cytokines; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; D010455:Peptides