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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细胞是自身免疫的效应细胞，它们迁移寻找目标，产生细胞因子招募和