Combining regulatory T cell depletion and inhibitory receptor blockade improves reactivation of exhausted virus-specific CD8+ T cells and efficiently reduces chronic retroviral loads.
Combining regulatory T cell depletion and inhibitory receptor blockade improves reactivation of exhausted virus-specific CD8+ T cells and efficiently reduces chronic retroviral loads.
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DOI：
10.1371/journal.ppat.1003798
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Dittmer U
中科院分区：
文献类型：
--
作者：
Dietze KK;Zelinskyy G;Liu J;Kretzmer F;Schimmer S;Dittmer U
慢性感染人类病毒，如艾滋病毒和丙型肝炎病毒，或小鼠病毒，如LCMV或Friend病毒(FV)，导致CD8+T细胞功能衰竭。目前已描述了两种主要机制来调节这种耗竭：CD8+T细胞上抑制性受体的表达和抑制CD8+T细胞活性的调节性T细胞(Tregs)的扩张。一些研究表明，阻断其中一个途径会导致CD8+T细胞重新激活，并部分减少慢性病毒载量。使用针对PD-1配体和TIM-3的封闭抗体以及可以选择性切除Tregs的转基因小鼠，我们比较了这两种治疗策略，并首次在慢性逆转录病毒感染模型中将它们结合起来。阻断抑制性受体在恢复耗竭的CD8+T细胞和降低病毒设定点方面比一过性耗尽Tregs更有效。然而，联合治疗优于任何单一治疗，进一步增强CD8+T细胞反应，并导致慢性病毒载量的持续减少。这些结果表明，Tregs和抑制性受体是维持慢性病毒感染的非重叠因素，针对这两条途径的免疫疗法可能是治疗慢性传染病的一种有前途的策略。功能丧失，即CD8+T细胞的“衰竭”，是许多慢性感染的一个特征。T细胞耗竭主要由两种机制介导，CD8+T细胞上抑制性受体的表达和病毒诱导的调节性T细胞(Tregs)的扩张，从而抑制CD8+T细胞的活性。几项小鼠研究显示，在阻断其中一条途径后，CD8+T细胞重新激活，慢性病毒载量减少。这些结果启动了一些主要针对癌症患者的临床研究，其中封闭抗体被用来干扰抑制性受体信号或耗尽Treg的药物。我们首次将这两种治疗方法结合起来，使用转基因小鼠，其中Tregs可以被选择性地消融，并在慢性逆转录病毒感染中注射阻断抗体。结果表明，联合疗法在进一步增强CD8+T细胞应答和降低慢性病毒载量方面优于任何单一疗法。我们的发现表明，Tregs和抑制性受体是维持慢性病毒感染的非重叠因素，针对这两条途径的免疫疗法可能是治疗慢性传染病的一种有前途的新策略。
Chronic infections with human viruses, such as HIV and HCV, or mouse viruses, such as LCMV or Friend Virus (FV), result in functional exhaustion of CD8+ T cells. Two main mechanisms have been described that mediate this exhaustion: expression of inhibitory receptors on CD8+ T cells and expansion of regulatory T cells (Tregs) that suppress CD8+ T cell activity. Several studies show that blockage of one of these pathways results in reactivation of CD8+ T cells and partial reduction in chronic viral loads. Using blocking antibodies against PD-1 ligand and Tim-3 and transgenic mice in which Tregs can be selectively ablated, we compared these two treatment strategies and combined them for the first time in a model of chronic retrovirus infection. Blocking inhibitory receptors was more efficient than transient depletion of Tregs in reactivating exhausted CD8+ T cells and reducing viral set points. However, a combination therapy was superior to any single treatment and further augmented CD8+ T cell responses and resulted in a sustained reduction in chronic viral loads. These results demonstrate that Tregs and inhibitory receptors are non-overlapping factors in the maintenance of chronic viral infections and that immunotherapies targeting both pathways may be a promising strategy to treat chronic infectious diseases. A loss of function, the so-called ‘exhaustion’ of CD8+ T cells, is a hallmark of many chronic infections. The T cell exhaustion is mediated by two main mechanisms, the expression of inhibitory receptors on CD8+ T cells and virus-induced expansion of regulatory T cells (Tregs), which suppress CD8+ T cell activity. Several mouse studies revealed a reactivation of CD8+ T cells and reduction in chronic viral loads after blockage of one of these pathways. These results initiated a number of clinical studies mainly with cancer patients, in which blocking antibodies were used to interfere with inhibitory receptor signaling or drugs that deplete Tregs. For the first time we combined the two therapeutic approaches by using transgenic mice in which Tregs can be selectively ablated and injection of blocking antibodies in a chronic retroviral infection. The results indicate that the combination therapy was superior to any single treatment in further augmenting CD8+ T cell responses and reducing chronic viral loads. Our findings demonstrate that Tregs and inhibitory receptors are non-overlapping factors in the maintenance of chronic viral infections and that immunotherapies targeting both pathways may be a promising new strategy to treat chronic infectious diseases.
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DOI：
10.4049/jimmunol.1202951
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期刊：
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影响因子：
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