PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8+ T lymphocytes in the liver
PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8+ T lymphocytes in the liver
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DOI：
10.4049/jimmunol.178.5.2714
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发表时间：
2007-03-01
影响因子：
4.4
通讯作者：
Chisari, Francis V.
中科院分区：
文献类型：
--
作者：
Maier, Holly;Isogawa, Masanori;Chisari, Francis V.
导致慢性病毒感染，包括慢性乙肝病毒感染的机制还不是很清楚。我们最近发现，一种重要的抗病毒细胞因子--干扰素-γ的产生在进入乙肝转基因小鼠的肝脏后迅速被诱导，然后被迅速抑制，尽管仍有抗原存在。CTL抑制干扰素-γ的产生与程序性细胞死亡(PD)-1的上调是一致的，PD-1是一种已知的抑制T细胞功能的细胞表面信号分子。为了确定PD-1是否在CTL分泌干扰素-γ的功能抑制中发挥作用，我们用PD-1配体(PD-L)1的特异性抗体阻断乙肝转基因小鼠，并过继转移乙肝病毒特异性CTL。用抗PD-L1抗体治疗后，肝脏中产生干扰素的CTL的抑制延迟，同时产生干扰素的CTL的绝对数增加。这些结果表明，PD-1：PD-L1相互作用有助于抑制肝脏中Ag识别后观察到的干扰素-γ的分泌。阻断抑制通路，如PD-1：PD-L1，在CTL反应被抑制的情况下，可能会逆转病毒的持久性和慢性感染。
Mechanisms contributing to the development of chronic viral infections, including chronic hepatitis B virus (HBV) infections, are not well understood. We have shown recently that production of IFN-gamma, an important antiviral cytokine, by HBV-specific CTLs is rapidly induced when they enter the liver of HBV transgenic mice, and then rapidly suppressed, despite the continued presence of Ag. Suppression of IFN-gamma production by the CTLs coincides with the up-regulation of programmed cell death (PD)-1, a cell surface signaling molecule known to inhibit T cell function. To determine whether PD-1 plays a role in the functional suppression of IFN-gamma secretion by CTLs, we treated HBV transgenic mice with blocking Abs specific for PD ligand (PD-L)1, the most widely expressed PD-1 ligand, and adoptively transferred HBV-specific CTLs. Treatment with anti-PD-L1 Abs resulted in a delay in the suppression of IFN-gamma-producing CTLs and a concomitant increase in the absolute number of IFN-gamma-producing CTLs in the liver. These results indicate that PD-1:PD-L1 interactions contribute to the suppression of IFN-gamma secretion observed following Ag recognition in the liver. Blockade of inhibitory pathways such as PD-1:PD-L1 may reverse viral persistence and chronic infection in cases in which the CTL response is suppressed by this mechanism.