Regulation of T Cell Activity During Chronic Infections

描述（由申请人提供）：CD 8 T细胞在控制细胞内病原体和防止致瘤细胞生长方面发挥关键作用;然而，可能会建立更长时间和持续性的感染。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缺陷性CD 8 T细胞反应的发展有关。在这些条件下，抗原特异性CD 8 T细胞的逐步和进行性功能失活导致应答细胞不能表型成熟为记忆T细胞。如果感染持续存在，那么这可能最终导致CD 8 T细胞的物理缺失。令人鼓舞的报告表明，如果可以在足够的时间范围内降低高病毒载量，则可以发生CD 8 T细胞效应活性的至少部分恢复，并且可以出现更典型的记忆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CD 8 T细胞集可能会增强对持续性病毒感染的免疫力。然而，抗病毒CD 8 T细胞效应子活性的进行性减少是否是发育编程的或仅由抗原丰度驱动的尚不明确，并且也不知道某些CD 8 T细胞亚群是否在感染的早期阶段对功能失活更具抗性。相反，目前尚不清楚功能受损的抗病毒CD 8 T细胞的所有亚群是否表现出类似的恢复效应活性的能力，以及这些功能再活化的CD 8 T细胞的保护功效是否与正常的静息记忆T细胞相匹配。我们将探讨这些问题，通过解决的假设，抗原负荷，结合细胞因子环境，作为一个电阻调节器的功能质量和抗病毒CD 8 T细胞的成熟状态。我们的具体目标是：（1）确定最佳致敏的CD 8 T细胞对功能耗竭的易感性;（2）确定抗原撤回和细胞因子环境对次佳CD 8 T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消退后是否产生真正的记忆性CD 8 T细胞。更持久和慢性的感染难以根除，特别是公共卫生问题。这些研究的结果可能会提供关于如何微调抗病毒CD 8 T细胞反应以更好地对抗持续感染的新信息，并且与我们制定控制潜在新兴病原体的策略的能力有关。

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.