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

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.

• Authors: Gang Cai, Xiaomeng Nie, Lei Li, Liang Hu, Beiying Wu, Jiafei Lin, Cen Jiang, Huaizhou Wang, Xuefeng Wang, Qian Shen
• Journal: Journal of gastroenterology (J Gastroenterol) Vol. 48 Issue 12 Pg. 1362-72 (Dec 2013) ISSN: 1435-5922 [Electronic] Japan
• PMID: 23532637 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BTLA protein, human
• Interleukin-2
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Receptors, Immunologic
• Interferon-gamma

Topics

• Adult
• Aged
• Cell Differentiation
• Dendritic Cells (immunology)
• Female
• Flow Cytometry
• Hepatitis B, Chronic (immunology, virology)
• Humans
• Interferon-gamma (immunology)
• Interleukin-2 (immunology)
• Leukocytes, Mononuclear (immunology)
• Male
• Middle Aged
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, metabolism)
• Receptors, Immunologic (antagonists & inhibitors, metabolism)
• T-Lymphocytes (immunology)
• Up-Regulation
• Young Adult