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

• DOI: 10.1007/s00535-013-0762-9
• Publication Date: 2013-03-26T16:43:57Z
• Authors: Gang Cai; Xiaomeng Nie; Lei Li; Liang Hu; Beiying Wu; Jiafei Lin; Cen Jiang; Huaizhou Wang; Xuefeng Wang; Qian Shen
• Keywords: Adult; Male; 0301 basic medicine; T-Lymphocytes; Programmed Cell Death 1 Receptor; Cell Differentiation; Dendritic Cells; Middle Aged; Flow Cytometry; Up-Regulation; 3. Good health; Interferon-gamma; Young Adult; 03 medical and health sciences; Hepatitis B, Chronic; Leukocytes, Mononuclear; Humans; Interleukin-2; Female; Receptors, Immunologic; Aged

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.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.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.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.