T cell exhaustion: a means or an end?
T cell exhaustion: a means or an end?
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DOI：
10.1038/ni.2619
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发表时间：
2013-05
影响因子：
30.5
通讯作者：
Shahram Salek-Ardakani;S. Schoenberger
中科院分区：
文献类型：
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作者：
Shahram Salek-Ardakani;S. Schoenberger
为了保护和服务于宿主，CD 8 + T淋巴细胞必须作为适应性免疫系统中最具适应性的应答者，能够将来自其环境、抗原呈递细胞、辅助细胞和靶细胞的无数信号整合成适当的效应器应答，以应对即将到来的免疫挑战，但不会有明显损害自身的风险。然而，在慢性病毒感染期间，它们对反复刺激和持续性炎症的反应似乎是“衰竭”的一种，这是一个涉及功能和存活的进行性丧失的过程，伴随着抑制性受体（如PD-1和LAG-3）的范围增加的表面表达，并最终导致凋亡死亡1。Utzschneider等人在本期《自然免疫学》杂志上的一份报告提出了这样一种可能性，即耗尽可能代表一种特异性和适应性的分化状态，而不是构成过度刺激的T细胞在死亡过程中的功能障碍状态。术语“衰竭”已被用于描述小鼠慢性病毒感染期间T细胞的功能无反应性、复制性衰老和最终物理缺失的状态3，4，并且已在小鼠和人类对肿瘤和慢性寄生虫和细菌感染的免疫应答中检测到5。该结果与急性感染诱导的结果形成鲜明对比，急性感染既可以产生多功能效应细胞来介导病原体清除，又可以产生持久的记忆成分，能够在次级（回忆）反应中产生新的效应细胞。疲惫的状态似乎是在对一系列抗原刺激的反应中逐渐发展的，这些抗原刺激将T细胞驱动到更深的无反应状态，通过这种无反应状态，关键功能，如增殖，细胞因子产生，细胞毒性以及最终的存活，逐渐丧失。衰竭的发展与许多负调控途径的表面受体的表达相一致，这些受体被认为控制其诱导和进展1。这些包括PD-1（其中），其表达似乎是功能性的，而不仅仅与耗竭相关，因为阻断PD-1及其配体PD-L1的途径可以恢复CD 8 + T细胞的功能和存活6。因此，PD-1 nEwS和vIEwS npg
To both protect and serve the host, CD8+ T lymphocytes must act as among the most adaptable responders of the adaptive immune system, able to integrate myriad signals from their environment, antigen-presenting cells, accessory cells and target cells into the appropriate effector response for the immunological challenge at hand but without risking overt damage to self. During chronic viral infection, however, their response to repeated stimulation and persistent inflammation seems to be one of‘exhaustion’, a process that involves a progressive loss of function and survival that is accompanied by surface expression of an increasing range of inhibitory receptors such as PD-1 and LAG-3 and, ultimately, apoptotic death1. The possibility that rather than constituting a dysfunctional state of overstimulated T cells on their way to dying, exhaustion may represent a specific and adaptive state of differentiation is raised by a report from Utzschneider et al. in this issue of Nature Immunology2. The term ‘exhaustion’has been used to describe the state of functional unresponsiveness, replicative senescence and ultimate physical deletion of T cells during chronic viral infection in mice3, 4 and has been detected in immune responses to tumors and chronic parasitic and bacterial infections of mice and humans5. That outcome contrasts with the outcome induced by acute infection, which can yield both polyfunctional effector cells to mediate pathogen clearance and a durable memory component that is able to generate new effector cells in secondary (recall) responses. The exhausted state seems to develop progressively in response to serial rounds of antigenic stimulation that drive T cells into deeper states of unresponsiveness through which key functions, such as proliferation, cytokine production, cytotoxicity and, finally, survival, are incrementally lost. The development of exhaustion coincides with the expression of surface receptors of many negative regulatory pathways, which are thought to control its induction and progression1. These include PD-1 (among others), whose expression seems to be functional and not merely correlative with exhaustion, as blockade of the pathway of PD-1 and its ligand PD-L1 can restore both functionality and survival to CD8+ T cells6. Thus, PD-1 nEwS AnD vIEwS npg