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反应的最终结果。我们认为，在最初的激活过程中，只有几个效应细胞的存活受到指导。由于无法准确识别哪些初级反应细胞将分化为记忆性T细胞，这一指导过程的特征受到了显著阻碍。最近，我们发现CD8aa+主效应子集上CD8α/α的表达是记忆性CD8 T细胞前体的唯一标志。这一新见解首次为评估CD8 T细胞记忆形成的教学过程提供了有力的工具。 在这项资助的第一个目标中，我们将确定树突状细胞(DC)的亚群和成熟阶段在产生CD8Alpha/Alpha+记忆前体群体中的作用。在第二个目标中，我们将解决T细胞帮助在CTL记忆产生中的作用。将调查传统的CD4Th帮助和NKT细胞提供的帮助的贡献。在第三个目标中，我们将关注CD8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CD8α/α+记忆前体细胞的初始选择，以及在重复抗原刺激过程中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以激发对感染和癌症的最佳免疫力，或者对抑制自身免疫或移植反应的治疗非常重要。这个方案中的实验使用了淋巴细胞性脉络膜脑膜炎病毒(LCMV)，一种竞技场病毒。了解CDS对病毒和其他病原体形成记忆的基本机制，与当今美国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.