Regulation of T Cell Activity During Chronic Infections

描述(由申请人提供)：深入了解调节CD8 T细胞反应的诱导、质量和寿命的内在和外在因素，对于设计合理的策略来对抗病毒感染和肿瘤是至关重要的，目前的预防和治疗方案对这些疾病的预防和治疗方案是不够的。鉴于效应性和记忆性CD8 T细胞反应在降低与细胞内感染和肿瘤相关的发病率和死亡率方面的生物学重要性，确定决定其功能质量、保护效果和持久性的因素至关重要。虽然抗病毒CD8 T细胞 细胞在它们的效应器功能组合中表现出不同，由于缺乏有效和高效的方法来分离、跟踪和定义基于它们的细胞因子产生谱的这些不同的亚集，对这一集合的剖析一直受到阻碍。因此，对于抗病毒CD8 T细胞的功能特征如何在发育过程中被印记，它们是否可以预测应答的有效性，以及这些固有特性如何调节效应器、记忆和疲惫群体的建立，我们的理解仍然存在重大差距。解决这些问题有可能改变我们的理解，即某些自然感染和疫苗为什么以及如何成功地引发保护性细胞免疫，以及为什么会发生流产和功能不全的反应，特别是在慢性感染期间。为了克服基于细胞因子产生模式分析不同CD8 T细胞亚群相关的障碍，我们开发并验证了双细胞因子报告系统，并表明使用这一策略很容易检测和分离功能离散的人群。这为在急性和慢性感染期间从功能上解构抗病毒CD8 T细胞提供了一种独特而强大的方法，这是使用传统技术几乎不可能实现的。我们现在将充分利用这个机会来确定CD8 T细胞功能差异在初始阶段(目标1)以及反应的效应和记忆阶段(目标2)的原因和后果。此外，我们还将确定最容易耗尽的CD8T细胞亚群，以及在免疫治疗后更能抵抗灭活和有效的抗病毒T细胞的功能特性(目标3)。鉴于CD8 T细胞在抗病毒防御中无处不在的作用，我们的研究旨在通过定义支配抗病毒CD8 T细胞功能异质性的共同免疫学原理，定义这一原理如何与免疫和病毒学结果相结合，并实际应用这些信息来促进和重新配置反应，从而有利于宿主防御，从而广泛影响该领域。

DESCRIPTION (provided by applicant): Developing an in-depth basic understanding of the intrinsic and extrinsic factors that regulate the induction, quality, and longevity of CD8 T cell responses is essential for devising rational strategies to combat viral infections and tumors for which current prevention and treatment regimens are inadequate. Given the biological importance of effector and memory CD8 T cell responses in reducing the morbidity and mortality associated with intracellular infections and tumors, it is paramount to define the factors that determine their functional quality, protective efficacy, and persistence. Although anti-viral CD8 T cells display differences in their portfolios of effector functions, dissecting this ensemble has been impeded by the lack of effective and efficient methods for segregating, tracking, and defining these distinct subsets based upon their cytokine production profiles. Consequently, vital gaps remain in our understanding of how the functional features of anti-viral CD8 T cells become developmentally imprinted, whether they forecast the efficacy of the response, and how these intrinsic properties regulate the establishment of effector, memory, and exhausted populations. Addressing these issues has the potential to transform our understanding of why and how successful protective cellular immunity is elicited by certain natural infections and vaccinations, and why abortive and functionally incompetent responses occur, especially during chronic infections. To overcome the obstacles associated with analyzing distinct CD8 T cell subsets based upon their patterns of cytokine production we have developed and validated double cytokine reporter systems, and have shown that functionally discrete populations are easily detectable and separable using this strategy. This provides a unique and powerful approach for functionally deconstructing the ensemble of anti-viral CD8 T cells during both acute and chronic infections, which has been almost impossible to achieve using conventional techniques. We will now take full advantage of this opportunity to determine the causes and consequences of CD8 T cell functional disparities during the inception (aim 1), as well as effector and memory (aim 2) phases of the response. In addition, we will define the subsets of CD8 T cells that are most susceptible to exhaustion, as well as the functional properties of anti-viral T cells that are more resistant to inactivation and efficacious following immunotherapy (aim 3). Given the ubiquitous roles of CD8 T cells in anti-viral defense our studies are designed to broadly impact the field by defining the common immunological principles that govern the functional heterogeneity of anti-viral CD8 T cells, defining how this is coupled to the immunological and virological outcome of the response, and practically applying this information to promote and reconfigure responses to favor host defense.