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细胞通常在用外源抗原引发幼稚T细胞后产生，但作为淋巴细胞减少环境中稳态增殖的结果，不同的途径也可以产生功能性记忆T细胞。通过稳态增殖产生的记忆T细胞（“HP记忆”细胞）的研究与理解记忆T细胞分化的基本要求相关，并且还与评估该替代途径在免疫受损个体中建立保护性免疫的相关性相关。使用小鼠模型，我们最近表明，“常规记忆”T细胞（即通过引发产生的T细胞）和HP记忆CD 8 T细胞都提供了类似的针对病原体的保护性免疫。然而，虽然淋巴细胞减少症的实验模型得到了很好的研究，但对淋巴细胞减少症的自然情况下（新生儿期和急性感染后）产生的HP记忆细胞知之甚少。我们在三个目标中对此进行了探索，研究：在“天然”淋巴细胞减少环境中产生的HP记忆CD 8 T细胞的功能（目标1）;抗原特异性内源性HP记忆CD 8 T细胞的存在和功能（目标2）;新生儿淋巴细胞减少症和内源性HP CD 8记忆T细胞在支持幼龄动物免疫反应性中的作用（目标3）。这些研究的目的是确定在淋巴细胞减少症的自然发作期间是否产生外源抗原应答性HP记忆CD 8 T细胞，以及它们是否有助于适应性免疫应答。公共卫生解放：记忆T细胞是抵抗病原体的免疫保护的关键因素。记忆细胞是由于免疫引发而产生的，但也在对免疫缺陷或淋巴细胞减少症的反应期间产生，这在发育期间生理上发生，也是感染的结果。该提议的意义在于了解这种“稳态”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”CD 8 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.