Helper-Dependent CD8 T Cell Memory

描述（由申请人提供）：记忆性CD8 T细胞作为适应性免疫系统的优秀哨兵，在赋予针对细胞内病原体以及致瘤细胞的免疫保护中发挥重要作用。功能性记忆CD8 T细胞区室的产生和维持受多种因素影响，包括诱导抗原、刺激程度和辅助细胞的存在。我们的实验室以及其他实验室已经证明，CD4 T细胞对于功能性记忆CD8 T细胞池的生成和维持至关重要，这些记忆CD8 T细胞的最佳配置用于保护目的。然而，目前尚不清楚CD4 T细胞的哪些亚群和特异性促进记忆性CD8 T细胞的分化、维持和保护潜力。此外，尚不清楚异质记忆性CD8 T细胞库的所有成分是否同样依赖于CD4 T细胞的帮助。拟议研究的目的是提供有关CD4 T细胞帮助建立记忆性CD8 T细胞应答的需求、记忆性T细胞数量和功能潜力的长期维持以及记忆性CD8 T细胞产生保护性次级应答的能力的新信息。我们假设，CD4 T细胞在反应的诱导阶段促进记忆性CD8 T细胞前体的产生，并且随后，CD4 T细胞支持能够参与回忆反应的功能性记忆性CD8 T细胞的稳定维持。为了解决这个问题，我们建议：（1）。确定不同的CD8 T细胞亚群是否需要CD4 T细胞帮助转变为记忆T细胞。（二）、确定用于产生和维持记忆性CD8 T细胞的不同CD4 T细胞亚群的要求。（三）、确定CD4 T细胞在继发性CD8 T细胞应答期间的影响。感染控制和疫苗设计的一个关键问题是确定如何配置和维持记忆T细胞的长寿命池，这些记忆T细胞在二次暴露后最有效地清除病原体。因此，确定CD4和CD8 T细胞之间的相互作用对于记忆性CD8 T细胞的形成、功能和持久性是必要的，具有基础和临床意义。最终，这些研究提供的信息可能会为旨在增强疫苗介导的保护性免疫以及增强由于CD4辅助性T细胞应答中的潜在缺陷而劣化的应答的翻译举措奠定基础。

DESCRIPTION (provided by applicant): Memory CD8 T cells serve as excellent sentinels of the adaptive immune system and play a prominent role in conferring immunological protection against intracellular pathogens as well as tumorigenic cells. The generation and maintenance of a functionally competent memory CD8 T cell compartment is influenced by multiple factors, including the inducing antigen, the degree of stimulation, and the presence of accessory cells. Our laboratory, as well as others, has documented that CD4 T cells are vital for the generation and maintenance of pools of functionally competent memory CD8 T cells that are optimally configured for protective purposes. It remains unclear, however, which subsets and specificities of CD4 T cells promote the differentiation, maintenance, and protective potential of memory CD8 T cells. Moreover, it is not known whether all constituents of heterogeneous memory CD8 T cell pools are equally dependent upon CD4 T cell help. The objective of the proposed studies is to provide new information regarding the requirements of CD4 T cell help for the establishment of memory CD8 T cell responses, the long term maintenance of memory T cell numbers and functional potential, and the ability of memory CD8 T cells to mount protective secondary responses. We hypothesize that CD4 T cells promote the generation of memory CD8 T cell precursors during the induction phase of the response and that, subsequently, CD4 T cells support the stable maintenance of functionally competent memory CD8 T cells that are capable of participating in recall responses. To address this we propose: (1). To determine whether distinct CD8 T cell subsets require CD4 T cell help to transition into memory T cells. (2). To define the requirements for distinct CD4 T cell subsets for the generation and maintenance of memory CD8 T cells. (3). To determine the impact of CD4 T cells during secondary CD8 T cell responses. A key issue for infection control and vaccine design is determining how to configure and sustain long-lived pools of memory T cells that are most effective at clearing pathogens following secondary exposures. Defining the interplay between CD4 and CD8 T cells that is necessary for the formation, function, and persistence of memory CD8 T cells is, therefore, of both fundamental and clinical relevance. Ultimately the information provided by these studies may form the foundation for translational initiatives designed to enhance vaccine-mediated protective immunity as well as boost responses that are inferior due to underlying defects in CD4 helper T cell responses.