Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection.
Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection.
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DOI：
10.1084/jem.20071949
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发表时间：
2008-03-17
期刊：
影响因子：
--
通讯作者：
Ahmed R
中科院分区：
文献类型：
--
作者：
Ha SJ;Mueller SN;Wherry EJ;Barber DL;Aubert RD;Sharpe AH;Freeman GJ;Ahmed R
治疗性疫苗接种是一种潜在的有前途的策略，可以增强慢性感染者的T细胞免疫和病毒控制。然而，治疗性疫苗接种方法没有达到预期的效果，并且并不总是观察到有效增强抗病毒T细胞反应。治疗性疫苗接种取得有限成功的主要原因之一是，病毒特异性T细胞在慢性感染期间功能耗尽。我们现在提供了一种新的策略来提高治疗性疫苗的功效。在这项研究中，我们发现阻断程序性死亡(PD)-1/PD- l1抑制信号在耗尽的CD8+ T细胞上，结合治疗性疫苗，协同增强CD8+ T细胞的功能反应，改善慢性淋巴细胞性脉络丛脑膜炎病毒感染小鼠的病毒控制。这种组合治疗性疫苗接种即使在没有CD4+ T细胞帮助的情况下也是有效的。因此，我们的研究定义了一种有效的新方法，通过阻断负面信号来增强治疗性疫苗的效力。这种方法可能在制定慢性感染的治疗策略方面有广泛的应用，也许也适用于肿瘤。
Therapeutic vaccination is a potentially promising strategy to enhance T cell immunity and viral control in chronically infected individuals. However, therapeutic vaccination approaches have fallen short of expectations, and effective boosting of antiviral T cell responses has not always been observed. One of the principal reasons for the limited success of therapeutic vaccination is that virus-specific T cells become functionally exhausted during chronic infections. We now provide a novel strategy for enhancing the efficacy of therapeutic vaccines. In this study, we show that blocking programmed death (PD)-1/PD-L1 inhibitory signals on exhausted CD8+ T cells, in combination with therapeutic vaccination, synergistically enhances functional CD8+ T cell responses and improves viral control in mice chronically infected with lymphocytic choriomeningitis virus. This combinatorial therapeutic vaccination was effective even in the absence of CD4+ T cell help. Thus, our study defines a potent new approach to augment the efficacy of therapeutic vaccination by blocking negative signals. Such an approach may have broad applications in developing treatment strategies for chronic infections in general, and perhaps also for tumors.
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