FoxP3+ T cells of mucosal tissues

描述(申请人提供)：维生素A(视黄醇)及其代谢物(称为维甲酸)在免疫系统中起着关键作用。维甲酸调节各种类型免疫细胞的发育和功能，并被用于治疗一些炎症性疾病和癌症。有强有力的证据表明，维生素A代谢物在免疫系统的调节中既有积极的作用，也有消极的作用，我们仍然不清楚它们是如何在这两种方式中发挥作用的。本研究的总体目标是阐明维甲酸在体外和体内粘膜组织中FoxP3+调节性T细胞生成中的作用，并确定这一新的生物途径的功能意义。Foxp3+调节性T细胞是T细胞的一个主要亚群，专门抑制自身免疫和过度活跃的免疫反应。我们的中心假设是，维甲酸是FoxP3+细胞的天然诱导者，FoxP3+细胞专门调节粘膜组织的免疫反应。这一假设是基于我们强大的初步数据显示，维甲酸诱导T细胞中的主要转录因子FoxP3。我们还发现，维甲酸诱导的FoxP3+细胞是独特的，因为它们表达粘膜组织归巢受体和几个与靶细胞杀伤相关的效应分子。我们这个项目的基本原理是，它的成功完成很可能为我们理解维甲酸作为免疫反应的自然调节器的作用提供一种重要的机制。这项应用有三个特定目标：特定目标#1：建立维甲酸作为粘膜FoxP3+调节性T细胞亚群的天然诱导剂。特定目的#2：确定维甲酸诱导的粘膜归巢FoxP3+T细胞组织趋向性的分子基础。具体目的#3：研究维甲酸诱导的FoxP3+T细胞对黏膜组织免疫反应和炎症反应的调节作用。随着拟议研究的成功完成，我们希望：1)确定维生素A代谢物调节免疫系统的新机制；2)确定维甲酸诱导的FoxP3+T细胞的重要运输受体；3)确定通过使用维生素A/维甲酸和维甲酸诱导的FoxP3+T细胞来控制选定粘膜组织中的炎症性疾病的新策略。 公共卫生相关性：我们将研究维生素A及其代谢物如何促进T细胞的产生，这些T细胞对免疫反应的调节至关重要。该项目的成果将极大地促进我们对粘膜组织中重要调节性T细胞亚群的产生以及维生素A和维甲酸在免疫和炎症性疾病调节中的作用的理解。由于维生素A被人类广泛消耗，该项目对人类健康的影响将很高。

DESCRIPTION (provided by applicant): Vitamin A (retinol) and its metabolites (called retinoids) play critical roles in the immune system. Retinoids regulate the development and functions of various types of immune cells and are being used as therapeutics for some inflammatory diseases and cancers. There is a strong body of evidence that vitamin A metabolites play both positive and negative roles in regulation of the immune system, and we still do not clearly understand how they function in both ways. The overall objective of this research is to elucidate the role of retinoids in generation of FoxP3+ regulatory T cells in mucosal tissues in vitro and in vivo and to determine the functional significance of this novel biological pathway. FoxP3+ regulatory T cells are a major subset of T cells specialized in suppression of autoimmunity and over-active immune responses. Our central hypothesis is that retinoids are natural inducers of FoxP3+ cells that are specialized in regulation of immune responses in mucosal tissues. This hypothesis is based upon our strong preliminary data showing that retinoids induce the master transcription factor FoxP3 in T cells. We also found that the retinoid-induced FoxP3+ cells are unique in that they express mucosal tissue homing receptors and several effector molecules associated with target cell killing. Our rationale for this project is that its successful completion may well provide a mechanism important for our understanding of the role of retinoids as natural regulators of immune responses. This application has three specific aims: Specific aim #1: Establish retinoids as natural inducers of a mucosal FoxP3+ regulatory T-cell subset. Specific aim #2: Determine the molecular basis of the tissue tropism of retinoid-induced mucosal homing FoxP3+ T cells. Specific aim #3: Investigate the impact of retinoid-induced FoxP3+ T cells on regulation of immune responses and inflammation in mucosal tissues. Following the successful completion of the proposed research, we expect to 1) have identified a novel mechanism by which vitamin A metabolites regulate the immune system; 2) have determined the important trafficking receptors of retinoid-induced FoxP3+ T cells; and 3) have identified novel strategies by which we can control inflammatory diseases in selected mucosal tissues through the use of vitamin A/retinoids and retinoid-induced FoxP3+ T cells. PUBLIC HEALTH RELEVANCE: We will study how vitamin A and its metabolites promote the generation of T cells important for regulation of immune responses. The outcomes of this project would significantly advance our understanding of the generation of important regulatory T cell subsets in mucosal tissues and of the roles of vitamin A and retinoids in regulation of the immunity and inflammatory diseases. Since vitamin A is widely consumed by humans, the impact of the project on human health will be high.