Autoreactive T Cell Function in Vitiligo

白癜风中的自身反应性 T 细胞功能

基本信息

批准号：
10703385
负责人：
SALLY Choate KENT
金额：
$ 50.69万
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：
2022
资助国家：
美国
起止时间：
2022-09-12 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10703385
关键词：
3-Dimensional Affect Affinity Animal Model Antigen Targeting Antigenic Specificity Antigens Autoimmune Diseases Autoimmunity Biological Assay Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Communication Cell Culture Techniques Cell Separation Cell physiology Cells Center for Translational Science Activities Characteristics Clinical Clonality Clone Cells Communication Complex Computing Methodologies Data Disease Effector Cell Epidermis Epigenetic Process Fluorescent in Situ Hybridization Gene Expression Profile Genetic Genetic Risk Human Immune Immunohistochemistry In Vitro Individual Infiltration Inflammatory Insulin-Dependent Diabetes Mellitus Lesion Location Maintenance Mediating Microtome - medical device Modeling Molecular Multiomic Data Multiple Sclerosis Organ Organ Culture Techniques Pathway interactions Patients Phenotype Pigments Play Population Positioning Attribute Proteins Regulatory T-Lymphocyte Resolution Role Sampling Signal Transduction Skin Slice Stable Disease T cell clonality T cell infiltration T cell receptor repertoire sequencing T cell response T-Cell Receptor T-Lymphocyte Testing Therapeutic Intervention Tissues Transcript Translational Research Trichrome stain method Vitiligo White Spots autoreactive T cell clinical phenotype cytokine cytotoxic cytotoxic CD8 T cells disease phenotype effector T cell health disparity human tissue in vivo melanocyte migration mouse model multiple omics novel therapeutic intervention programs recruit response restraint risk variant single-cell RNA sequencing skin disorder skin lesion spatial relationship tool vibration

项目摘要

T cells are effector cells of autoimmunity that migrate to find their targets, produce cytokines that recruit and activate other immune cells, and destroy their target cells in affected tissue. Vitiligo is an autoimmune disease of the skin in which cytotoxic CD8+ T cells target pigment-making melanocytes, which results in disfiguring white spots that are particularly devastating for those with darker skin and thus leads to health disparities for the most vulnerable of our population. Vitiligo is an ideal disease in which to investigate mechanisms of organ- specific autoimmunity because disease phenotype can be directly correlated to molecular pathways. That is, affected skin can be observed and sampled, target cells and antigens are known, and translational research tools are available. Vitiligo shares genetic risk alleles and other mechanisms with autoimmune diseases like type 1 diabetes and multiple sclerosis that are more difficult to study in human patients. Through vitiligo we can develop a comprehensive understanding of organ-specific autoimmunity as it progresses within human tissue. In vitiligo and models of other human autoimmune diseases, autoreactive T cell responses are commonly char- acterized as homogenous, with an “all or nothing” result. This is partly due to the fact that mouse models of autoimmunity are frequently based on a single high-affinity CD8+ cytotoxic clone transferred and activated arti- ficially. However, we found that T cells infiltrating vitiligo skin lesions are polyclonal and heterogeneous, with different antigenic specificities and activation states. Cytotoxic CD8+ T cells organize into clustered units within the epidermis that appear to attack melanocytes, while CD4+ and Treg cells are at the periphery of these clus- ters. Together, these data indicate that T cell interactions in vitiligo are more complex than previously under- stood. Our central hypothesis is that polyclonal CD8+, CD4+, and Treg cell communications coordinate mela- nocyte destruction and determine vitiligo clinical phenotypes. This project will determine how autoreactive T cell clonal diversity and localization define the clinical disease phenotype, how T cell subtypes interact with each other to coordinate autoimmunity, and how T cells orches- trate melanocyte destruction within the skin. First, we will determine the in vivo location, spatial relationships, and functional characteristics of T cell clones in different clinical phenotypes of vitiligo, such as early incipient vs. late established lesions, active vs. stable disease, and single vs. multiple locations. Next, we will character- ize the function and reactivity of T cells isolated directly from the skin of these lesions. We will use primary T cell and skin organ culture, T cell functional assays, T cell receptor affinity assays, the sequential fluorescence in situ hybridization (seqFISH+) Core, and advanced computational methods. This project is translational in approach because it will create new mechanistic understanding of how T cells mediate the initiation, progres- sion, and maintenance of autoimmunity during vitiligo. Together these aims will define molecular mechanisms utilized by autoreactive T cells and identify key functional pathways, supporting new therapeutic interventions.

T细胞是自身免疫性的效应细胞，迁移以找到其靶标，产生募集和激活其他免疫细胞，并在受影响组织中破坏其靶细胞。白癜风是一种自身免疫性疾病细胞毒性CD8+ T细胞靶向色素生产黑素细胞的皮肤，这导致毁容对于皮肤较暗的人来说，白点特别具有毁灭性，从而导致健康分布我们最脆弱的人群。白癜风是一种理想的疾病，可以研究器官的机制特定的自身免疫性，因为疾病表型可以与分子途径直接相关。那是，可以观察到受影响的皮肤，并采样，靶细胞和抗原，并翻译研究可以使用工具。白癜风与自身免疫性疾病具有遗传风险等位基因和其他机制 1型糖尿病和多发性硬化症在人类患者中更难研究。通过白癜风我们可以随着器官特异性自身免疫的全面了解，它在人体组织中的发展。在白癜风和其他人类自身免疫性疾病的模型中，自动反应性T细胞反应通常是char- 被化为同质的，带有“全或全无”的结果。这部分是由于以下事实自身免疫性经常基于单个高亲和力CD8+细胞毒性克隆转移和激活的艺术家 - 身体上。但是，我们发现浸润白化病皮肤病变的T细胞是多克隆和异质性的，具有不同的抗原规格和激活状态。细胞毒性CD8+ T细胞组织成聚类的单位似乎攻击黑素细胞的表皮，而CD4+和Treg细胞处于这些clus-的外围 Ters。总之，这些数据表明白癜风中的T细胞相互作用比以前不足的情况更为复杂我们的中心假设是多克隆CD8+，CD4+和Treg细胞通信坐标旋律 - 诺西特破坏并确定白癜风临床表型。该项目将确定自动反应性T细胞克隆多样性和定位如何定义临床疾病表型，T细胞亚型如何相互相互作用以协调自身免疫性，以及T细胞如何管弦乐皮肤中的微型黑素细胞破坏。首先，我们将确定体内位置，空间关系， T细胞克隆在不同临床表型中的功能特征，例如早期初期与较晚的病变，活性与稳定疾病以及单个位置与多个位置。接下来，我们将角色 ize直接从这些病变的皮肤中分离出的T细胞的功能和反应性。我们将使用主要t 细胞和皮肤器官培养，T细胞功能测定，T细胞受体亲和力测定，顺序荧光原位杂交（Seqfish+）核心和高级计算方法。这个项目是翻译的方法是因为它会对T细胞如何介导主动性的新机械理解，白癜风期间的自身免疫性和维持自身免疫性。这些目的共同定义分子机制由自动反应性T细胞使用并确定关键功能途径，支持新的治疗干预措施。