Selective Instructions for Memory Precursor T Cells

描述（由申请人提供）：记忆T细胞的产生是产生性免疫反应的最终结果。我们认为，在初始激活过程中，只有少数效应细胞的存活受到指示。由于无法准确识别哪些主要应答细胞将分化为记忆T细胞，这一教学过程的表征受到了极大的阻碍。最近，我们已经证明cd8α / α在CD8aa+主要效应子的选定子集上的表达独特地标记了记忆性CD8 T细胞的前体。这一新发现首次为评估CD8 T细胞记忆形成的指导过程提供了一个强有力的工具。

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.