Characterization of Type-2 Cytokine-Producing NK Cells

描述(由申请人提供)：过敏性免疫反应偏向于产生2型细胞因子。我们已经确定了一小部分人类自然杀伤(NK)细胞的新表面标记，这些细胞产生2型细胞因子IL-4和IL-13。此外，我们还表明，这些2型NK细胞在特应性人类受试者的肺中富含，以响应过敏原的攻击。因此，我们的数据表明，这些细胞可能参与了致敏部位的炎症反应，如肺和胃肠道的粘膜表面。我们发现了更好的表面标记来描绘这些细胞，这使我们能够更好地纯化它们并确定它们的功能。在这一应用中，我们建议进行探索性研究，以显著提高我们对2型NK细胞生物学的理解。具体地说，我们将1)对人类2型NK细胞上的受体进行分类，并测试它们对生物反应的影响，以及2)利用我们在人类中的知识来表征小鼠的2型NK细胞，并测试它们是否也能对哮喘小鼠模型的过敏性挑战做出反应。这些发现将填补我们对调节2型NK细胞功能的环境信号的理解方面的重大空白，并建立一个研究其体内功能的小鼠模型。对这些生物学参数的深入了解将使我们能够确定2型NK细胞在局部过敏反应和感染的发病机制中的作用，特别是在呼吸道和肠道。基于我们的发现，未来的研究将能够确定分子靶点，以操纵2型NK细胞的功能，以改善人类健康。公共卫生相关性：对公共健康而言，自然杀伤(NK)细胞是正常的白细胞，可以刺激先天免疫反应。我们最近发现了表面标志物来定义一小部分NK细胞，这些细胞在接触过敏原后可以进入人类志愿者的肺部。这些细胞是独一无二的，因为它们可以产生可能导致过敏性炎症的可溶性因子，因此，我们将在人类和小鼠中进一步研究这些细胞，以确定它们在人类健康和疾病中的作用。

DESCRIPTION (provided by applicant): Allergic immune responses are biased toward the production of type-2 cytokines. We have identified new surface markers of a small subset of human natural killer (NK) cells that produce the type-2 cytokines, IL-4 and IL-13. In addition, we have shown that these type-2 NK cells are enriched in the lungs of atopic human subjects in response to allergenic challenge. Therefore, our data suggest that these cells may contribute to the inflammatory response at sites of allergenic insult, such as mucosal surfaces of the lung and gastrointestinal tract. Our discovery of better surface markers to delineate these cells allows us to better purify them and define their functions. In this application, we propose exploratory studies to significantly improve our understanding of the biology of type-2 NK cells. Specifically, we will 1) catalog receptors on the human type-2 NK cells and test their impacts on biological responses, and 2) use our knowledge in humans to characterize the type-2 NK cells in mice and test whether they can also respond to allergenic challenge in a mouse model of asthma. The findings will fill significant gaps in our understanding of environmental signals that regulate the functions of type-2 NK cells, and establish a mouse model for studying their in vivo functions. Improved understanding of these biological parameters will allow us to establish the roles of type-2 NK cells in the pathogenesis of localized allergic responses and infections, particularly in the respiratory and intestinal tracts. Future studies, based upon our findings, will be able to identify molecular targets to manipulate the functions of type-2 NK cells to improve human health. PUBLIC HEALTH RELEVANCE: to Public Health Natural killer (NK) cells are normal white blood cells that can stimulate innate immune responses. We have recently discovered surface markers to define a small subset of NK cells that can enter the lungs of human volunteers after exposure to an allergen. These cells are unique, since they can produce soluble factors that may contribute to allergic inflammation, and therefore, we will further study these cells in humans and mice to establishing their role in human health and disease.