Generation and Function of NK Cell Memory

抗原(Ag)特异性记忆的形成是疫苗成功和免疫治疗的关键 感染和癌症，但携带免疫记忆的细胞也与许多人类 疾病。T和B细胞一直被认为是免疫记忆的唯一载体，所以努力诊断， 治疗或预防免疫性疾病一直集中在这些淋巴细胞上。然而，有越来越多的人 这一以T和B细胞为中心的范例需要修改的证据：初步研究表明， 记忆也可以通过肝脏驻留的自然杀伤(NK)细胞的离散子集获得，这些细胞产生于 在遇到提呈抗原的树突状细胞(DC)时的淋巴结(LN)。到目前为止，NK记忆一直是 记录了四种不同的半抗原和六种病毒抗原。这个项目的目标是阐明 从机制上讲，这种新的NK细胞的功能，并了解其病理生理后果。二 将追求特定的目标：目标1将研究记忆NK细胞的机制和后果 在LNS中引爆。为此，我们将描述具有天真记忆能力的NK细胞亚群(S)和 研究提供抗原特异性的分子机制；我们将分析NK细胞的动力学 与LNS中的DC的相互作用；我们将探索人类NK细胞是否也能获得记忆。目标2 将以半抗原和流感病毒为模型表征预置NK细胞的召回反应。在这里，我们 将调查稳定状态和重新挑战时的记忆NK细胞运输；分析记忆NK细胞 流感感染过程中的介导性保护；并探讨负共刺激在记忆NK中的作用 细胞的生成、持久性和功能。

The formation of antigen (Ag)-specific memory is key for the success of vaccines and for immunotherapy of infections and cancer, but the cells that carry immunological memory are also implicated in numerous human disease. T and B cells have been considered sole carriers of immunological memory, so efforts to diagnose, treat or prevent immune diseases have been focused on these lymphocytes. However, there is mounting evidence that this T and B cell-centric paradigm requires revision: preliminary work has shown that long-lived memory can also be acquired by a discrete subset of liver-resident natural killer (NK) cells, which arise in lymph nodes (LNs) upon encounter of Ag presenting dendritic cells (DCs). To date, NK memory has been documented for four distinct haptens and six viral Ags. The goals of this project are to elucidate mechanistically this novel NK cell function and to understand its pathophysiological consequences. Two specific aims will be pursued: Aim 1 will investigate the mechanisms and consequences of memory NK cell priming in LNs. To this end, we will characterize the 'naive' memory-capable NK cell subset(s) and investigate the molecular mechanism that provides Ag-specificity; we will analyze the dynamics of NK cell interactions with DCs In LNs; and we will explore whether human NK cells can also acquire memory. Aim 2 will characterize recall responses of primed NK cells using haptens and influenza virus as models. Here, we will investigate memory NK cell trafficking at steady state and upon rechallenge; analyze memory NK cell mediated protection during influenza infection; and explore the role of negative costimulation in memory NK cell generation, persistence and function.