Homeostatic Proliferation and Memory CD8 T Cells

T细胞记忆的产生是保护性免疫的关键组成部分，但细胞和分子 建立功能性T细胞记忆所涉及的要求知之甚少。而记忆T细胞 通常发生在用外来抗原启动初始T细胞后，也可以产生一种不同的途径 功能性记忆T细胞--在淋巴细胞减少的环境中体内平衡增殖的结果。 体内平衡增殖产生的记忆T细胞(“HP记忆”细胞)的研究与 了解记忆T细胞分化的基本要求，并评估 这一替代途径在免疫受损个体建立保护性免疫中的相关性。 利用小鼠模型，我们最近发现，两种“常规记忆”T细胞(即那些产生的T细胞 通过启动)和HP Memory CDS T细胞对病原体提供类似的保护性免疫。也喜欢 传统的记忆性CDS T细胞，HP记忆性CDS T细胞的功能依赖于它们接受CD4T 细胞在他们那一代的“帮助”。然而，这种CD4帮助的确切性质和有缺陷的基础 “无助的”记忆CDS细胞(即那些没有CD4T细胞产生的细胞)的反应仍然不清楚。 此外，CD4细胞的作用和无助记忆CDS细胞的特征似乎都是 HP下的记忆路径与传统的记忆路径不同。我们在这项建议中的主要目标是1) 建立在产生功能性HP Memory CDS T细胞过程中的CD4“Help”的性质；2)确定 无助的HP Memory CDS T细胞功能缺陷的基础和3)将这些研究扩展到 HP记忆细胞在生理条件下产生的特性。

Generation of T cell memory is a critical component of protective immunity, yet the cellular and molecular requirements involved in establishing functional T cell memory are poorly understood. While memory T cells normally arise following priming of naive T cells with foreign antigen, a distinct pathway can also generate functional memory T cells - as a consequence of homeostatic proliferation in a lymphopenic environment. Study of memory T cells produced by homeostatic proliferation ("HP memory" cells) is relevant to understanding the essential requirements for memory T cell differentiation, and also for assessing the relevance of this alternative pathway in establishing protective immunity in immunocompromized individuals. Using mouse models, we recently showed that both "conventional memory" T cells (i.e. those generated through priming) and HP memory CDS T cells offer similar protective immunity against a pathogen. Also like conventional memory CDS T cells, the function of HP memory CDS T cells depends on them receiving CD4 T cell "help" during their generation. However, the exact nature of this CD4 help and the basis for the defective response of "helpless" memory CDS cells (i.e. those generated without CD4 T cells) is still unclear. Furthermore, both the role of CD4 cells and the characteristics of helpless memory CDS cells appears to be different under HP versus conventional memory pathways. Our main goals in this proposal are to 1) establish the nature of CD4 "help" during generation of functional HP memory CDS T cells; 2) determine the basis for defective function of helpless HP memory CDS T cells and 3) to extend these studies into looking at the properties of HP memory cells which arise during physiological conditions.