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：
9753126
负责人：
John E Harris
金额：
$ 36.85万
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/9753126
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（由适用提供）：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）中起关键作用。大多数针对Treg功能的研究是在体外或次级淋巴机构（SLOS）中进行的，对Treg在外周组织中的功能知之甚少。 Treg必须首先识别正确的组织，找到炎症的重点，然后与效应T细胞（TEFF）共定位，但是如何在外周组织中有效地进行此操作。该提议中的中心假设是Tregs需要趋化因子信号和组织特异性的树突状细胞相互作用，以查找和调节周围组织中的TEFF。这些机制不能在外周组织之外进行适当的研究，因此需要一个体内特定器官特异性自身免疫模型，我们创建了一种自身免疫性皮肤疾病的小鼠模型，其中CXCL10需要将TEFF转移到皮肤和表皮驱动疾病中。我们已经使用一般修饰的小鼠，皮肤流式细胞术和共聚焦显微镜广泛开发了该模型，将我们的观察结果与人体组织相关，以便在自身免疫期间更好地了解T细胞功能。为了检验我们的假设，我们将在白癜风的小鼠模型中进行功能研究，并将这些发现与人白癜风皮肤样品的现有生物库相关联。我们发现Treg抑制了白癜风并将其定位于我们的小鼠模型中的CXCL10。我们假设Treg是由CXCL10招募的，以与TEFF共定位并抑制其功能。我们将在AIM 1中对此进行测试，我们将确定Tregs是否需要TEFF，是否需要CXCL10受体CXCR3，以及人类Treg在皮肤中的treg定位是否预测白化严重程度。我们将在AIM 2中对此进行测试，我们将确定Teff/Treg互动是否使用LHC是抗原特异性的，CXCL10是否稳定其相互作用，以及在人白癜风皮肤中发生Teff-Treg-LHC相互作用的频率。在没有Treg或LHC的情况下，在白癜风期间，Teff在皮肤中大量积累，与增殖无关。我们假设Tregs直接促进了皮肤的Teff出口。我们将在AIM 3中对此进行测试，在AIM 3中，我们将定义Treg抑制后TEFF的表型，确定Tregs是否促进了Teff从皮肤中促进Teff出口，并将小鼠和人白癜风中调节的TEFF的免疫类型相关。白癜风是研究基本机制的理想模型，通过这种机制，Tregs在自身免疫期间抑制周围组织中的Teffs。这项工作有可能定义可以作为多种器官特异性自身免疫性疾病的新治疗策略定义途径。