Regulation of T Cell Activity During Chronic Infections

描述（由申请人提供）：CD8 T细胞在控制细胞内病原体和防止致瘤细胞的生长中起关键作用；然而，更长期和持续的感染可以建立。我们的实验室以及其他实验室已经证明，无法快速清除某些病毒感染与CD8 T细胞反应缺陷的发展有关。在这些条件下，随着应答细胞未能在表型上成熟为记忆T细胞，抗原特异性CD8 T细胞的功能逐渐失活。如果感染持续，那么这可能最终导致CD8 T细胞的物理缺失。令人鼓舞的报告表明，如果高病毒载量可以在足够的时间内减少，那么至少可以部分恢复CD8 T细胞效应活性，并且可能出现更多典型的记忆T细胞。因此，确定如何促进、维持和潜在地重新激活强大的抗病毒CD8 T细胞，可能会增强对持续病毒感染的免疫力。然而，目前尚不清楚的是，抗病毒CD8 T细胞效应活性的逐渐减弱是由发育程序决定的，还是仅仅由抗原丰度驱动的，而且也不清楚在感染的早期阶段，CD8 T细胞的某些亚群是否更能抵抗功能失活。相反，目前尚不清楚是否所有功能受损的抗病毒CD8 T细胞亚群都表现出类似的恢复效应活性的能力，以及这些功能重新激活的CD8 T细胞的保护功效是否与正常的静止记忆T细胞相匹配。我们将通过解决抗原负荷与细胞因子环境一起作为抗病毒CD8 T细胞功能质量和成熟状态的流变调节剂的假设来研究这些问题。我们的具体目标是：(1)确定最佳启动的CD8 T细胞对功能衰竭的敏感性；(2)确定抗原退出和细胞因子环境对亚优CD8 T细胞亚群表型和功能特性的影响；(3)确定长时间病毒感染消退后是否会产生真正的记忆性CD8 T细胞。较长期和慢性的感染难以根除，是一个特别令人关切的公共卫生问题。这些研究的发现可能提供关于如何微调抗病毒CD8 T细胞反应以更好地对抗持续感染的新信息，并且与我们设计控制潜在新出现病原体的策略的能力相关。

DESCRIPTION (provided by applicant): CD8 T cells play a critical role in controlling intracellular pathogens and preventing the outgrowth of tumorigenic cells; however, more prolonged and persistent infections can become established. Our laboratory, as well as others, have documented that the inability to rapidly clear certain viral infections is associated with the development of defective CD8 T cell responses. Under these conditions a stepwise and progressive functional inactivation of antigen-specific CD8 T cells ensues as the responding cells fail to phenotypically mature into memory T cells. If the infection persists then this may culminate in the physical deletion of the CD8 T cells. Encouraging reports suggest that if high viral loads can be reduced, within a sufficient timeframe, then at least a partial restoration of CD8 T cell effector activities can occur and more typical memory T cells may emerge. Determining how to promote, sustain, and potentially reactivate robust sets of anti-viral CD8 T cells is, therefore, likely to enhance immunity to persistent viral infections. Nevertheless, it is ill-defined whether the progressive diminution of anti-viral CD8 T cell effector activities is developmentally programmed or solely driven by antigen abundance, and it is also not known if certain subsets of CD8 T cells are more resistant to functional inactivation during the early stages of infection. Conversely, it is unclear whether all subsets of functionally impaired anti-viral CD8 T cells exhibit a similar capability of regaining effector activities and whether the protective efficacy of these functionally reactivated CD8 T cells matches that of normal, resting memory T cells. We will investigate these issues by addressing the hypothesis that antigen load, in conjunction with the cytokine milieu, serves as a rheostatic regulator of the functional quality and maturation state of anti-viral CD8 T cells. Our specific aims are: (1) To determine the susceptibility of optimally primed CD8 T cells to functional exhaustion; (2) To determine the impact of antigen withdrawal and cytokine milieu on the phenotypic and functional properties of sub-optimal CD8 T cell subsets; (3) To determine whether bona fide memory CD8 T cells develop following the resolution of prolonged viral infections. More protracted and chronic infections are difficult to eradicate and are of particular public health concern. The findings of these studies are likely to provide new information regarding how anti-viral CD8 T cell responses can be fine-tuned to better combat persistent infections, and are relevant to our ability to devise strategies to control potential emerging pathogens.