Blockade of Tim-3 signaling restores the virus-specific CD8+ T-cell response in patients with chronic hepatitis B

Authors

  • Wei Wu,

    1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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    • The author contributes to this work equally.

  • Yu Shi,

    1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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    • The author contributes to this work equally.

  • Shuping Li,

    1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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  • Yun Zhang,

    1. Department of Emergency Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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  • Yanning Liu,

    1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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  • Yihua Wu,

    1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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  • and Zhi Chen

    Corresponding author
    1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
    • Full correspondence Dr. Zhi Chen, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China

      Fax: +86-0571-87068731

      e-mail: zju.zhichen@gmail.com

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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-3CD8+ 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.

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