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

• 批准号: 9539195
• 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
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9539195
• 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' 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; human tissue; in vivo Model; migration; mouse model; public health relevance; recruit; response; skin disorder; skin lesion; treatment strategy

 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(申请人提供)：T调节细胞(Tregs)在控制器官特异性自身免疫性疾病中发挥关键作用，包括1型糖尿病、多发性硬化症和白癜风。大多数针对Treg功能的研究都是在体外或在次级淋巴器官(SLO)中进行的，对Treg在周围组织中的功能知之甚少。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(TeFs)共定位，但这在周围组织中是如何有效完成的尚不清楚。该方案的中心假设是Tregs需要趋化因子信号和组织特异性树突状细胞相互作用来发现和调节周围组织中的Teffs。这些机制不能在外周组织外进行适当的研究，因此需要器官特异性自身免疫的体内模型来定义它们。我们创建了一种自身免疫性皮肤病白癜风的小鼠模型，在该模型中，CXCL10需要引导TJeff迁移到皮肤和表皮以驱动疾病。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一模型，将我们的观察结果与人类组织相关联，以便更好地了解T细胞在自身免疫期间的功能。为了验证我们的假设，我们将在白癜风小鼠模型中进行功能研究，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。在我们的小鼠模型中，我们发现Tregs抑制白癜风并定位于CXCL10。我们假设Tregs是由CXCL10招募来与Teffs共定位并抑制其功能的。我们将在Aim 1中测试这一点，在那里我们将确定Treg是否随Teffs迁移，他们是否需要CXCL10受体CXCR3，以及人类Treg在皮肤中的定位是否预测白癜风的严重程度。我们发现朗格汉斯细胞(LHC)是白癜风期间皮肤中产生CXCL10的主要细胞，是表皮Treg积累所必需的，也是控制疾病所必需的。我们假设Tregs和Teffs需要通过TCR-MHC相互作用和CXCL10与LHC拴在一起，以促进它们的共同定位。我们将在Aim 2中测试这一点，在那里我们将确定TJeff/Treg交互作用 与LHC的相互作用是抗原特异性的，CXCL10是否稳定了它们的相互作用，以及TJeff-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，Teffs在白癜风期间会在皮肤中大量积累，不依赖于细胞的增殖。我们假设Tregs直接促进皮肤中的Teff排泄。我们将在目标3中测试这一点，在那里我们将定义Tregs抑制后Teffs的表型，确定Tregs是否促进皮肤中的Tef外泄，并将调节Teffs在小鼠和人类白癜风中的免疫表型相互关联。白癜风是研究Tregs在自身免疫过程中抑制外周组织中Teffs的基本机制的理想模型。这项工作有可能确定可作为多器官特异性自身免疫性疾病的新治疗策略的途径。