Selective Instructions for Memory Precursor T Cells

描述（由申请人提供）：记忆T细胞的产生是生产性免疫应答的最终结果。我们提出，在初始激活过程中，只有少数效应细胞的存活受到指示。这种指导过程的表征由于无法精确地鉴定哪些初级应答细胞将分化为记忆T细胞而受到严重阻碍。最近，我们已经表明，CD 8aa+主要效应子的选定子集上的CD 8 α/α表达独特地标记了记忆性CD 8 T细胞的前体。这一新的见解首次提供了一个强大的工具来评估CD 8 T细胞记忆形成的教学过程。 在本基金的第一个目标中，我们将定义树突状细胞（DC）的亚群和成熟阶段在产生CD 8 α/α +记忆前体群体中的作用。在第二个目标中，我们将讨论T细胞在CTL记忆产生中的作用。将研究常规CD 4 Th辅助和NKT细胞提供的辅助的贡献。在第三个目标中，我们将关注CD 8效应T细胞本身，并评估TCR激活信号的质量在多大程度上有助于CD 8 α/α +记忆前体细胞的初始选择以及在重复抗原刺激期间的进一步选择和克隆间竞争。 阐明导致有效记忆的初始事件对于设计疫苗和药物非常重要，这些疫苗和药物可以刺激对感染和癌症的最佳免疫力，或者抑制自身免疫或移植反应的治疗方法。本提案中的实验使用淋巴细胞性脉络丛脑膜炎病毒（LCMV），一种竞技场病毒。了解CDS记忆形成病毒和其他病原体的基本机制与美国今天面临的生物防御需求高度相关。

DESCRIPTION (provided by applicant): The generation of memory T cells is the end result of a productive immune response. We propose that the survival of just a few effector cells is instructed during the initial activation process. Characterization of this instructional process has been significantly hampered by the inability to identify precisely which primary responder cells will differentiate into memory T cells. Recently we have shown that CD8alpha/alpha expression on a selected subset of CD8aa+ primary effectors uniquely marks the precursors of memory CD8 T cells. This new insight provides for the first time a powerful tool to evaluate the instructional process of CD8 T cell memory formation. In the first Aim of this grant we will define the role of subsets and maturation stages of Dendritic Cells (DC) in generating the CD8alpha/alpha+ memory precursor population. In a second Aim, we will address the role of T cell help in the generation of CTL memory. The contributions of conventional CD4 Th help and help provided by NKT cells will be investigated. In a third Aim we will focus on the CD8 effector T cells themselves, and evaluate the extent to which the quality of the TCR activation signals contributes to the initial selection of CD8alpha/alpha+ memory precursor cells and to the further selection and interclonal competition during repeated antigenic stimulations. Elucidating the initial events that lead to effective memory are extremely important for the design of vaccines and drugs that stimulate optimal immunity against infections and cancers, or treatments that dampen the response in autoimmunity or transplantation. The experiments in this proposal use lymphocytic choriomeningitis virus (LCMV), an arena virus. Understanding the basic mechanism of CDS memory formation to viruses and other pathogenic agents is highly relevant to the biodefense needs facing the United States today.