Blockade of Tim-3 signaling restores the virus-specific CD8+ T-cell response in patients with chronic hepatitis B
Blockade of Tim-3 signaling restores the virus-specific CD8+ T-cell response in patients with chronic hepatitis B
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阻断 Tim-3 信号传导可恢复慢性乙型肝炎患者的病毒特异性 CD8 T 细胞反应
DOI：
10.1002/eji.201141852
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发表时间：
2012-05-01
影响因子：
5.4
通讯作者：
Chen, Zhi
中科院分区：
文献类型：
--
作者：
Wu, Wei;Shi, Yu;Chen, Zhi
慢性乙型肝炎（CHB）的特点是功能受损的病毒特异性CD8+ t细胞反应。然而，这种功能障碍的机制尚未完全阐明。我们研究了一种新发现的蛋白，t细胞免疫球蛋白结构域和含粘蛋白结构域的分子-3 (Tim-3)，在调节慢性乙型肝炎患者抗病毒CD8+ t细胞反应中的作用。用流式细胞术检测20例慢性乙型肝炎患者和20例健康对照者外周血病毒特异性CD8+ T细胞中Tim-3的表达。比较Tim-3+CD8+和Tim-3-CD8+ T细胞的表型和细胞因子产生能力。我们还研究了Tim-3信号对细胞增殖和细胞因子产生能力的影响。Tim-3在乙型肝炎病毒（HBV）特异性CD8+ T细胞中的表达高于巨细胞病毒（CMV）特异性CD8+ T细胞。Tim-3+ CD8+ T细胞在抗原刺激下表现出增生性衰老表型，细胞因子产生减少。最后，阻断Tim-3通路可显著改善CD8+ T细胞对hbv特异性抗原肽的增殖和抗病毒细胞因子分泌。Tim-3负调控慢性乙型肝炎患者分离的CD8+ T细胞的抗病毒反应，阻断Tim-3通路可逆转这种反应。
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-3-CD8+ 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.