Helper-Dependent CD8 T Cell Memory

描述（由申请人提供）：记忆性CD8 T细胞是适应性免疫系统的优秀哨兵，在对细胞内病原体和致瘤细胞的免疫保护中发挥着重要作用。功能性记忆CD8 T细胞区室的产生和维持受到多种因素的影响，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研究人员已经证明，CD4 T细胞对于产生和维持具有功能能力的记忆性CD8 T细胞至关重要，这些记忆性CD8 T细胞具有最佳的保护功能。然而，目前尚不清楚CD4 T细胞的哪些亚群和特异性促进了记忆性CD8 T细胞的分化、维持和保护潜力。此外，尚不清楚异质性记忆CD8 T细胞池的所有成分是否同样依赖于CD4 T细胞的帮助。本研究的目的是提供关于CD4 T细胞帮助建立记忆性CD8 T细胞应答、记忆性T细胞数量和功能潜能的长期维持以及记忆性CD8 T细胞发起保护性继发性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，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细胞帮助转化为记忆T细胞。（2）. 定义记忆性CD8 T细胞的产生和维持对不同CD4 T细胞亚群的需求。(3)。确定CD4 T细胞在继发性CD8 T细胞反应中的影响。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长寿命的记忆T细胞池，使其在二次暴露后最有效地清除病原体。因此，定义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为旨在增强疫苗介导的保护性免疫以及促进由于CD4辅助T细胞应答的潜在缺陷而较差的应答的转化倡议奠定基础。

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.