Homeostatic Proliferation and Memory CD8 T Cells

描述（由申请人提供）：T细胞记忆的产生是保护性免疫的关键组成部分。虽然记忆T细胞通常是在初始T细胞被外源抗原启动后产生的，但一个独特的途径也可以产生功能性记忆T细胞，这是淋巴细胞减少环境中稳态增殖的结果。研究由稳态增殖产生的记忆T细胞（“HP记忆”细胞）有助于理解记忆T细胞分化的基本要求，也有助于评估这一替代途径在免疫受损个体中建立保护性免疫的相关性。通过小鼠模型，我们最近发现“传统记忆”T细胞（即通过启动产生的T细胞）和HP记忆CD8 T细胞对病原体具有相似的保护性免疫。然而，尽管淋巴细胞减少的实验模型已经得到了很好的研究，但在淋巴细胞减少的自然情况下（新生儿期和急性感染后）产生的HP记忆细胞却知之甚少。我们在三个方面对此进行了探讨：在“自然”淋巴细胞减少环境中产生的HP记忆CD8 T细胞的功能（目的1）；抗原特异性内源性HP记忆CD8 T细胞的存在和功能（目的2）；新生儿淋巴细胞减少和内源性HP CD8记忆T细胞在支持幼龄动物免疫反应性中的作用（目的3）。这些研究的目的是确定在淋巴细胞减少的自然发作期间是否产生外源抗原反应性HP记忆CD8 T细胞，以及它们是否有助于适应性免疫反应。公共卫生相关性：记忆T细胞是免疫保护对抗病原体的关键因素。记忆细胞的产生是免疫启动的结果，但在对免疫缺陷或淋巴细胞减少的反应中也会产生，这在生理上发生在发育过程中，也可能是感染的结果。该建议的意义在于了解这种“体内平衡”机制如何在免疫受损个体（包括非常年轻的个体）中促进保护性“记忆样”CD8 T细胞系统的建立。

DESCRIPTION (provided by applicant): Generation of T cell memory is a critical component of protective immunity. While memory T cells normally arise following priming of naove 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 CD8 T cells offer similar protective immunity against a pathogen. However, while experimental models of lymphopenia are well studied, much less is known about HP memory cells produced during natural situations of lymphopenia (in the neonatal period and after acute infections). We explore this in three aims, studying: the function of HP memory CD8 T cells generated in "natural" lymphopenic environments (Aim 1): the presence and function of antigen specific endogenous HP memory CD8 T cells (Aim 2) and the role of neonatal lymphopenia and endogenous HP CD8 memory T cells in supporting immune reactivity of the young animals (Aim 3). The goal of these studies is to determine whether foreign antigen responsive HP memory CD8 T cells are generated during natural bouts of lymphopenia, and whether they contribute to the adaptive immune response. PUBLIC HEALTH RELEVENCE: Memory T cells are a critical element in immune protection against pathogens. Memory cells are generated as a consequence of immune priming, but are also generated during the response to immuno-deficiency, or lymphopenia, which occurs physiologically during development and also as a consequence of infections. The significance of the proposal is in learning how such "homeostatic" mechanisms may foster establishment of protective "memory- like" CD8 T cells system in immunocompromized individuals, including the very young.