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肿瘤细胞生长方面发挥关键作用；然而，可以建立更长期和持续的感染。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，随着应答细胞不能表型成熟为记忆性T细胞，抗原特异性CD8 T细胞的功能逐渐失活。如果感染持续下去，最终可能会导致CD8 T细胞的物理删除。令人鼓舞的报告表明，如果高病毒载量能够在足够的时间内减少，那么至少可以部分恢复CD8T细胞效应器的活动，并可能出现更典型的记忆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细胞集可能会增强对持续病毒感染的免疫力。然而，目前尚不清楚抗病毒CD8T细胞效应器活性的进行性降低是由发育编程还是单纯由抗原丰度驱动的，也不清楚CD8T细胞的某些亚群是否对感染早期的功能失活更具抵抗力。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动的能力，以及这些功能重新激活的CD8 T细胞的保护效果是否与正常的静止记忆T细胞相匹配。我们将通过以下假设来研究这些问题：抗原负载与细胞因子环境一起，作为抗病毒CD8T细胞功能质量和成熟状态的抗流变调节器。我们的具体目标是：(1)确定最佳启动的CD8T细胞对功能衰竭的敏感性；(2)确定抗原撤除和细胞因子环境对次优CD8T细胞亚群的表型和功能特性的影响；(3)确定在长期病毒感染后是否会形成真正的记忆CD8T细胞。更持久和更慢性的感染很难根除，尤其是公共卫生问题。这些研究的发现可能会提供有关如何微调抗病毒CD8 T细胞反应以更好地对抗持续感染的新信息，并与我们设计策略控制潜在新兴病原体的能力有关。

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.