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B and T lymphocyte attenuator is highly expressed on intrahepatic T cells during chronic HBV infection and regulates their function

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

T cell antiviral function is impaired during chronic hepatitis B (CHB). Programmed death-1 (PD-1) impairs antiviral T cell responses, but dysfunction is not always reversed by blockade of PD-1 pathway. Whether distinct T cell populations expressing different sets of inhibitory molecules exist has not been determined.

Methods

We studied the expression of the B and T lymphocyte attenuator (BTLA) on both peripheral blood mononuclear cells (PBMC) and intrahepatic lymphocytes, and the effects of blocking BTLA on circulating and intrahepatic T cells in CHB patients. Sixty-three CHB patients who underwent liver biopsy were enrolled. The expression of BTLA and PD-1 on PBMC and intrahepatic T cells was assessed by flow cytometry with antibodies to T cell differentiation molecules. Functional recovery was evaluated by analyzing production of interferon (IFN)-γ and interleukin (IL)-2 after incubation of T cells with anti-CD3 and irradiated mature dendritic cells in the presence of anti-BTLA, anti-PD-1, or both.

Results

Intrahepatic T cells expressed higher levels of BTLA than their peripheral counterparts. A significant fraction of intrahepatic T cells coexpressed BTLA and PD-1 and showed deep exhaustion of T cell responses. Blockade of the BTLA pathway enhanced both intrahepatic and PBMC T cell proliferation and cytokine secretion, and exhibited an additive effect upon blockage of PD-1.

Conclusions

Upregulation of inhibitory receptor BTLA restricts T cell responses in CHB. T cell exhaustion by high antigen concentrations exacerbates dysfunction of peripheral and intrahepatic T cells. Blockage of BTLA is a potential therapeutic approach for chronic HBV infection that may act by restoring antiviral T cell responses.

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Acknowledgments

This work was supported by grant 81001331 (to GC) from National Natural Science Foundation of China.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai, 200025, People’s Republic of China

    Gang Cai, Liang Hu, Beiying Wu, Jiafei Lin, Cen Jiang & Xuefeng Wang

  2. Department of Respiratory Diseases, Changhai Hospital, The Second Military Medical University, Shanghai, People’s Republic of China

    Xiaomeng Nie

  3. Department of Clinical Pathology, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai, People’s Republic of China

    Lei Li

  4. Department of Experimental Diagnosis, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People’s Republic of China

    Huaizhou Wang & Qian Shen

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  1. Gang Cai
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Correspondence to Gang Cai or Qian Shen.

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Cai, G., Nie, X., Li, L. et al. B and T lymphocyte attenuator is highly expressed on intrahepatic T cells during chronic HBV infection and regulates their function. J Gastroenterol 48, 1362–1372 (2013). https://doi.org/10.1007/s00535-013-0762-9

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  • DOI: https://doi.org/10.1007/s00535-013-0762-9

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