Hormonal Regulation of Immune Responses

CRTh2-PGD2通路介导细胞功能的许多稳态方面，包括趋化性、细胞因子表达和粘液产生。CRTh2在许多细胞类型中表达，但其调控主要在T淋巴细胞中被研究。CD4+ T淋巴细胞表达CRTh2是Th2细胞完全分化的标志，产生特征性的2型细胞因子，介导怀孕期间的免疫耐受、脂肪生物生成和组织修复等生理反应。自2005年以来，我的实验室一直在研究CRTh2及其在Th2细胞生物学中的作用。利用人类细胞中调控元件的全基因组图谱，我们开发了一种以细胞类型特异性方式研究CRTh2分子调控的方法。对这些区域的分析表明，在T细胞中，CRTh2可能受糖皮质激素（GC）皮质醇和性激素雌激素的调节。支持这一点，我们的功能数据表明，Th2细胞对GC的反应在雌激素存在下增强，可能涉及活性氧（ROS）的诱导。我们的假设是，激素通过影响CRTh2和Th2细胞的性别特异性功能来调节T细胞的命运及其在免疫中的作用。本研究旨在确定Th2细胞如何受到皮质醇的调节，以及是否存在基于雌激素暴露和/或生物性别的差异。为此，我们将研究激素对CRTh2表达和信号传导、Th2细胞功能、ROS产生和细胞代谢的控制，以及一个专门的组织内Th2亚群的发育。我们将描述女性和男性Th2细胞的反应，以确定一般和性别特异性的影响。使用Th2细胞作为实验范例将揭示以前未被认识的生理反应，有助于crth2介导的信号传导，并使我们能够研究细胞对ROS的控制如何调节其功能。意义：我们的发现将具有广泛的生物学意义，因为它们将与许多其他表达CRTh2的细胞类型和系统相关，并利用ros介导的信号传导进行细胞调节。我们的研究将主要由研究生和本科生进行，因此也将有助于我培养下一代科学家的目标，并向他们灌输在研究免疫反应时纳入生物性别的重要性。

The CRTh2-PGD2 pathway mediates many homeostatic aspects of cellular function including chemotaxis, cytokine expression and mucous production. CRTh2 is expressed by a number of cell types, though its regulation has been studied mainly in T lymphocytes. Expression of CRTh2 by CD4+ T lymphocytes is a marker of a fully differentiated Th2 cells producing the characteristic type 2 cytokines that mediate physiologic responses such as immune tolerance during pregnancy, fat biogenesis and tissue repair. My laboratory has been studying CRTh2 and its role in Th2 cell biology since 2005. Using whole genome maps of regulatory elements in human cells, we developed an approach to study the molecular regulation of CRTh2 in a cell type-specific manner. Analysis of these regions show that in T cells CRTh2 may be regulated by the glucocorticoid (GC) cortisol and the sex hormone estrogen. Supporting this, our functional data suggest Th2 cell response to GC is enhanced in the presence of estrogen and may involve induction of reactive oxygen species (ROS). It is our hypothesis that hormones regulate T cell fate and their role in immunity by influencing CRTh2 and Th2 cell function in a sex-specific manner. This study is designed to determine how Th2 cells are regulated by cortisol and whether there are differences based on estrogen exposure and/or biological sex. To do this, we will examine hormonal control of CRTh2 expression and signaling, Th2 cell function, ROS production and cellular metabolism and development of a specialized tissue-residing Th2 subset. We will characterize responses of both female and male Th2 cells, to identify general and sex-specific effects. Using Th2 cells as an experimental paradigm will reveal previously unappreciated physiologic responses contributing to CRTh2-mediated signaling and allow us to study how cellular control of ROS regulates their function. Significance: Our findings will be of broad biologic interest as they will be relevant to the many other cell types and systems expressing CRTh2 and utilizing ROS-mediated signaling for cellular regulation. Our study will be carried out primarily by graduate and undergraduate students and so will also facilitate my goal of training the next generation of scientists and instilling in them the importance of incorporating biological sex when studying immune responses.