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2型细胞因子的产生。我们已经确定了一小部分产生2型细胞因子，IL-4和IL-13的人类自然杀伤（NK）细胞的新的表面标记。此外，我们已经表明，这些2型NK细胞在应对过敏性挑战的特应性人类受试者的肺部富集。因此，我们的数据表明，这些细胞可能有助于过敏性损伤部位的炎症反应，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定义它们的功能。在本应用中，我们提出探索性研究，以显著提高我们对2型NK细胞生物学的理解。具体来说，我们将1)编目人类2型NK细胞上的受体，并测试它们对生物反应的影响，2)利用我们在人类身上的知识来表征小鼠中的2型NK细胞，并测试它们是否也能对哮喘小鼠模型中的过敏原挑战做出反应。这一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的重大空白，并建立小鼠模型来研究其体内功能。提高对这些生物学参数的理解将使我们能够确定2型NK细胞在局部过敏反应和感染发病机制中的作用，特别是在呼吸道和肠道中。未来的研究，基于我们的发现，将能够确定分子靶点来操纵2型NK细胞的功能，以改善人类健康。自然杀伤细胞（NK）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记来定义一小部分NK细胞，这些细胞可以在接触过敏原后进入人类志愿者的肺部。这些细胞是独特的，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.