Treg Migration and Function During Autoimmunity within Peripheral Tissue

周围组织内自身免疫过程中 Treg 的迁移和功能

基本信息

批准号：
9984020
负责人：
John E Harris
金额：
$ 0.1万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9984020
关键词：
Address Affect Antigens Apoptosis Area Autoimmune Diseases Autoimmune Process Autoimmunity CXC chemokine receptor 3 CXCL10 gene CXCR3 gene Cell Communication Cell physiology Confocal Microscopy Crohn&apos s disease Dendritic Cells Disease Epidermis Eragrostis Event Flow Cytometry Goals Human Immunophenotyping In Situ In Vitro Inflammation Inflammatory Bowel Diseases Insulin-Dependent Diabetes Mellitus Langerhans cell Learning Lymphoid MHC Interaction Mediating Modeling Multiple Sclerosis Mus Organ Organ Model Pathway interactions Patients Pattern Peripheral Phenotype Play Regulatory T-Lymphocyte Role Sampling Severities Signal Transduction Skin T-Cell Receptor T-Lymphocyte Testing Thyroid Diseases Tissues Ulcerative Colitis Vitiligo Work biobank chemokine disorder control effector T cell human tissue in vivo Model migration mouse model public health relevance recruit response skin disorder skin lesion treatment strategy

项目摘要

DESCRIPTION (provided by applicant): T regulatory cells (Tregs) play a critical role in controlling organ-specific autoimmune diseases, including type 1 diabetes, multiple sclerosis, and vitiligo. Most studies that address Treg function are performed in vitro or in secondary lymphoid organs (SLOs), and little is known about how Tregs function within peripheral tissues. Tregs must first identify the correct tissue, find the focus of inflammation, and then co-localize with effector T cells (Teffs), yet how this is done efficiently in peripheral tissues is unknown. Te central hypothesis in this proposal is that Tregs require chemokine signals and tissue-specific dendritic cell interactions to find and regulate Teffs within peripheral tissues. These mechanisms cannot be appropriately studied outside of peripheral tissues, and therefore require an in vivo model of organ-specific autoimmunity to define them. We created a mouse model of the autoimmune skin disease vitiligo, in which CXCL10 is required to direct Teff migration into skin and epidermis to drive disease. We have extensively developed this model using genetically modified mice, skin flow cytometry, and confocal microscopy, correlating our observations to human tissues in order to better understand T cell function during autoimmunity. To test our hypothesis, we will perform functional studies in our mouse model of vitiligo and correlate these findings to an existing biobank of human vitiligo skin samples. We found that Tregs suppress vitiligo and localize to CXCL10 in our mouse model. We hypothesize that Tregs are recruited by CXCL10 to co-localize with Teffs and suppress their function. We will test this in Aim 1, where we will determine whether Tregs migrate with Teffs, if they require the CXCL10 receptor CXCR3, and whether human Treg localization in the skin predicts vitiligo severity. We found that Langerhans cells (LHCs) are major producers of CXCL10 in the skin during vitiligo, are required for epidermal Treg accumulation, and for control of disease. We hypothesize that Tregs and Teffs require tethering to LHCs through TCR-MHC interactions and CXCL10 to promote their co-localization. We will test this in Aim 2, where we will determine whether Teff/Treg interactions with LHCs is antigen-specific, whether CXCL10 stabilizes their interaction, and how frequently Teff-Treg-LHC interactions occur in human vitiligo skin. In the absence of Tregs or LHCs, Teffs accumulate in large numbers in the skin during vitiligo, independent of proliferation. We hypothesize that Tregs directly promote Teff egress from the skin. We will test this in Aim 3, where we will define the phenotype of Teffs after suppression by Tregs, determine whether Tregs promote Teff egress from the skin, and correlate the immunophenotype of regulated Teffs in mouse and human vitiligo. Vitiligo serves as an ideal model to investigate fundamental mechanisms by which Tregs suppress Teffs within peripheral tissues during autoimmunity. This work has the potential to define pathways that can be targeted as a new treatment strategy for multiple organ-specific autoimmune diseases.

描述（由申请人提供）：T 调节细胞 (Treg) 在控制器官特异性自身免疫性疾病（包括 1 型糖尿病、多发性硬化症和白癜风）中发挥着关键作用，大多数涉及 Treg 功能的研究都是在体外或二级淋巴中进行的。人们对Tregs如何在外周组织中发挥作用知之甚少，Tregs必须首先识别正确的组织，找到炎症的焦点，然后与效应T细胞共定位。 (Teffs)，但如何在外周组织中有效地完成这一过程尚不清楚，该提议的中心假设是 Treg 需要趋化因子信号和组织特异性树突细胞相互作用来发现和调节外周组织内的 Teffs。 Teff 位于外周组织之外，因此需要器官特异性自身免疫的体内模型来定义它们。我们创建了自身免疫性皮肤病白癜风的小鼠模型，其中需要 CXCL10 来引导 Teff 迁移到皮肤和皮肤中。我们使用转基因小鼠、皮肤流式细胞仪和共聚焦显微镜广泛开发了这个模型，将我们的观察结果与人体组织相关联，以便更好地了解自身免疫期间的 T 细胞功能。我们在小鼠白癜风模型中进行了研究，并将这些发现与现有的人类白癜风皮肤样本生物库相关联，我们发现 Tregs 抑制白癜风并在我们的小鼠模型中定位于 CXCL10。由 CXCL10 招募来与 Teff 共定位并抑制其功能，我们将在目标 1 中对此进行测试，我们将确定 Tregs 是否与 Teff 一起迁移、它们是否需要 CXCL10 受体 CXCR3，以及人类 Treg 在皮肤中的定位是否可以预测白癜风。我们发现朗格汉斯细胞 (LHC) 是白癜风期间皮肤中 CXCL10 的主要产生者，是表皮 Treg 积累和维持所需的。我们勇敢地承认，Treg 和 Teff 需要通过 TCR-MHC 相互作用和 CXCL10 与 LHC 结合，以促进它们的共定位，我们将在目标 2 中对此进行测试，以确定 Teff/Treg 是否存在相互作用。 Teff-Treg-LHC 与 LHC 的相互作用具有抗原特异性，CXCL10 是否稳定它们的相互作用，以及 Teff-Treg-LHC 相互作用在人类白癜风皮肤中发生的频率。在没有 Tregs 或 LHC 的情况下，Teff 在白癜风期间在皮肤中大量积累，与增殖无关。我们追求Tregs直接促进Teff从皮肤中排出，我们将在目标3中对此进行测试，我们将在Tregs抑制后定义Teffs的表型，确定Tregs是否促进。 Teff 从皮肤中排出，并与小鼠和人类白癜风中受调节的 Teff 的免疫表型相关联，是研究 Tregs 在自身免疫过程中抑制外周组织内 Teff 的基本机制的理想模型。有望成为多器官特异性自身免疫性疾病的新治疗策略。