FoxP3+ T cells of mucosal tissues

描述（由申请人提供）：维生素A（视黄醇）及其代谢产物（称为类维生素A）在免疫系统中起关键作用。类维生素A调节各种类型的免疫细胞的发育和功能，并被用作一些炎性疾病和癌症的治疗剂。有大量证据表明，维生素A代谢物在免疫系统的调节中起着积极和消极的作用，我们仍然不清楚它们是如何以两种方式发挥作用的。本研究的总体目标是阐明类维生素A在体外和体内粘膜组织中产生FoxP 3+调节性T细胞中的作用，并确定这种新的生物学途径的功能意义。FoxP 3+调节性T细胞是专门抑制自身免疫和过度活跃的免疫应答的T细胞的主要亚群。我们的中心假设是类维生素A是FoxP 3+细胞的天然诱导物，FoxP 3+细胞专门调节粘膜组织中的免疫应答。这一假设是基于我们强有力的初步数据，表明类维生素A诱导T细胞中的主转录因子FoxP 3。我们还发现类维生素A诱导的FoxP 3+细胞是独特的，因为它们表达粘膜组织归巢受体和与靶细胞杀伤相关的几种效应分子。我们对这个项目的理由是，它的成功完成很可能提供了一个重要的机制，为我们的理解维甲酸作为免疫反应的天然调节剂的作用。本申请具有三个具体目的：具体目的#1：建立类维生素A作为粘膜FoxP 3+调节性T细胞亚群的天然诱导剂。具体目标#2：确定类维生素A诱导的粘膜归巢FoxP 3 + T细胞的组织嗜性的分子基础。具体目标#3：研究类维生素A诱导的FoxP 3 + T细胞对粘膜组织中免疫应答和炎症调节的影响。在成功完成拟议的研究之后，我们期望1）确定维生素A代谢物调节免疫系统的新机制; 2）确定类维生素A诱导的FoxP 3 + T细胞的重要运输受体;和3）已经确定了新的策略，通过使用维生素A/类维生素A和类维生素A诱导的FoxP 3+来控制选定粘膜组织中的炎症性疾病T细胞。 公共卫生相关性：我们将研究维生素A及其代谢产物如何促进T细胞的产生，T细胞对免疫反应的调节至关重要。该项目的结果将大大推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和类维生素A在免疫和炎症性疾病调节中的作用的理解。由于维生素A被人类广泛消费，该项目对人类健康的影响将很大。

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.