IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection
IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection
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DOI：
10.1073/pnas.0811139106
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发表时间：
2008-12-23
影响因子：
11.1
通讯作者：
Oldstone, Michael B. A.
中科院分区：
文献类型：
--
作者：
Brooks, David G.;Ha, Sang-Jun;Oldstone, Michael B. A.
宿主衍生的调节因子对T细胞应答的抑制是导致病毒持续存在的关键事件。在病毒持续存在期间，IL-10或程序性死亡配体1（PD-L1）的抗体阻断增强T细胞功能并降低病毒滴度。由于这些免疫调节网络的阻断代表了在持续感染期间建立免疫控制的有力方法，因此重要的是确定这些免疫抑制因子是否独立或联合作用，以及这些因子的联合阻断是否进一步增强T细胞免疫和病毒清除。在此，我们证明了IL-10和PD-L1免疫抑制途径在机制上是不同的。因此，IL-10和PD-L1的同时阻断在恢复抗病毒T细胞应答方面比单独阻断任何一种都显著更有效，并导致对已建立的持续性病毒感染的控制显著增强。因此，多种免疫调节分子的组合阻断可以最终恢复T细胞应答，所述T细胞应答是使平衡从病毒持续性向免疫介导的控制或消除持续性感染倾斜所需的。
Suppression of T-cell responses by host-derived regulatory factors is a key event leading to viral persistence. Antibody blockade of either IL-10 or programmed death-ligand 1 (PD-L1) during viral persistence enhances T-cell function and reduces viral titers. Because blockade of these immunoregulatory networks represents a powerful approach to establish immune control during persistent infection, it is important to determine whether these immunoinhibitory factors act independently or jointly and if combined blockade of these factors further enhances T-cell immunity and viral clearance. Herein, we demonstrate that the IL-10 and PD-L1 immunosuppressive pathways are mechanistically distinct. As a result, simultaneous blockade of IL-10 and PD-L1 was significantly more effective in restoring antiviral T-cell responses than blockade of either alone, and led to substantially enhanced control of an established persistent viral infection. Thus, combinatorial blockade of multiple immune-regulatory molecules may ultimately restore the T-cell responses required to tip the balance from viral persistence to immune-mediated control or elimination of persistent infection.