在慢性HBV感染B和T淋巴细胞衰减高表达对肝内T细胞和调节它

StephenW

Journal of Gastroenterology
December 2013, Volume 48, Issue 12, pp 1362-1372
B and T lymphocyte attenuator is highly expressed on intrahepatic T cells during chronic HBV infection and regulates their function


        Gang Cai [email protected] (1)
        Xiaomeng Nie (2)
        Lei Li (3)
        Liang Hu (1)
        Beiying Wu (1)
        Jiafei Lin (1)
        Cen Jiang (1)
        Huaizhou Wang (4)
        Xuefeng Wang (1)
        Qian Shen [email protected] (4)

Author Affiliations

        1. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai, 200025, People’s Republic of China
        2. Department of Respiratory Diseases, Changhai Hospital, The Second Military Medical University, Shanghai, People’s Republic of China
        3. Department of Clinical Pathology, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai, People’s Republic of China
        4. Department of Experimental Diagnosis, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People’s Republic of China


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.

StephenW

中华消化内镜杂志
2013年12月，第48卷，第12期，页1362至1372年
在慢性HBV感染B和T淋巴细胞衰减高表达对肝内T细胞和调节它们的功能


        刚蔡[email protected] （ 1 ）
        李小萌聂（ 2 ）
        雷力（ 3 ）
        胡亮（ 1 ）
        吴北英（ 1 ）
        嘉菲林（ 1 ）
        岑江（ 1 ）
        Huaizhou王（ 4 ）
        雪峰王（ 1 ）
        谦慎[email protected] （ 4 ）

作者所属机构

        1 。检验医学，瑞金医院，上海交通大学医学院，上海， 200025 ，中华人民共和国系
        2 。呼吸系统疾病的第二军医大学长海医院，上海，中华人民共和国
        3 。临床病理科，瑞金医院，上海交通大学医学院，上海，中华人民共和国
        4 。实验诊断的第二军医大学长海医院，上海， 200433 ，中华人民共和国


摘要
背景

慢性乙型肝炎（CHB ）在T细胞的抗病毒功能受损。程序性死亡-1 （PD- 1）损害抗病毒的T细胞应答，但功能障碍不总能得到的PD- 1途径阻断逆转。是否表示不同组的抑制分子的不同的T细胞群存在尚未确定。
方法

我们研究了两个外周血单核细胞（PBMC）和肝内淋巴细胞的B和T淋巴细胞衰减因子（ BTLA ）的表达，并阻断BTLA对循环和肝内T细胞在慢性乙型肝炎患者的影响。六十三CHB患者谁接受肝活检的患者。 BTLA和PD - 1的外周血单个核细胞及肝内T细胞的表达，用流抗体的T细胞分化的分子评估流式细胞仪。功能恢复通过分析生产干扰素（IFN） -γ，白细胞介素（ IL）的评价-2的T细胞用抗CD3孵化后和在抗BTLA的存在下照射成熟树突状细胞，抗PD- 1 ，或两者。
结果

肝内T细胞表达BTLA的水平高于其周边的同行。肝内T细胞的一个显著部分共表达BTLA和PD - 1和表现出的T细胞应答深耗尽。封锁BTLA途径增强肝内和PBMC中的T细胞增殖和细胞因子分泌的，并表现出在PD- 1的阻断累加效应。

结论

抑制性受体BTLA的上调限制在慢性乙型肝炎T细胞反应。 T细胞耗竭高抗原浓度加剧周边及肝内T细胞的功能障碍。 BTLA的堵塞是慢性乙肝病毒感染，可能通过恢复抗病毒T细胞反应扮演一个潜在的治疗方法。