GILT and regulation of Treg development in cutaneous autoimmunity

GILT 和皮肤自身免疫中 Treg 发育的调节

基本信息

批准号：
8913674
负责人：
KAREN TARASZKA HASTINGS
金额：
$ 7.58万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-10 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8913674
关键词：
Address Affect Antigen Presentation Antigen-Presenting Cells Antigens Appearance Atopic Dermatitis Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Award Bone Marrow Cell Differentiation process Cell physiology Cells Cellular Immunity Chimera organism Cutaneous Data Development Disease Enzymes Equilibrium Etiology Genetic Health Home environment Immunodeficient Mouse Inflammatory Interferon Type II Intervention Knowledge Lead Ligands Location Lymphoid Tissue MHC Class I Genes MHC Class II Genes Mediating Modeling Mus Organ Oxidoreductase Pathway interactions Peripheral Pilot Projects Play Prevention Process Psoriasis Regulation Regulatory T-Lymphocyte Role Self Tolerance Severities Site Skin Sulfhydryl Compounds Systemic Lupus Erythematosus T-Cell Receptor T-Lymphocyte Testing Therapeutic Transgenes Transgenic Mice Tyrosinase related protein-1 United States United States National Institutes of Health Vitiligo Work antigen processing clinically relevant clinically significant differentiation enhancing factor disulfide bond enhancing factor human TYRP1 protein human disease innovation lymph nodes melanoma mouse Tyrp1 protein mouse model novel novel therapeutic intervention prevent tool

项目摘要

DESCRIPTION (provided by applicant): Regulatory T (Treg) cells play a critical role in the prevention of cutaneous autoimmune and inflammatory diseases, such as vitiligo, psoriasis, atopic dermatitis and systemic lupus erythematosus. T cell receptor stimulation is a major factor which determines Treg cell differentiation. Therefore, manipulations of antigen processing pathways which diminish T cell receptor ligands may be used to enhance Treg cell development and lessen autoimmune disease. GILT (gamma-interferon-inducible lysosomal thiol reductase) is a prime candidate for such manipulation, because loss of GILT diminishes the presentation of a subset of antigens on MHC class I and II. The long term objective of this project is to determine how antigen processing pathways regulate the balance between T cell-mediated immunity and self-tolerance in the skin. GILT is an enzyme in the lysosomal compartment of antigen presenting cells that is critical for efficient processing of disulfide bond- containing antigens. Our prior studies have shown that GILT is required for MHC class II-restricted presentation of tyrosinase-related protein 1 (TRP1), a clinically-relevant autoantigen in vitiligo and melanoma. We have developed a TRP1-specific T cell receptor transgenic mouse model in which skin-specific Treg cells develop and suppress vitiligo. We hypothesize that the loss of GILT increases peripheral induction of Treg cells that home to the skin and control cutaneous autoimmune responses. In the current proposal we will employ a unique set of genetic and immunological tools to determine the etiology of increased Treg cells in the absence of GILT by investigating whether there is increased intrathymic Treg cell development, peripheral induction of Treg cells, or proliferation of Treg cells in the periphery. We will identify the factors that lad to increased Treg cells in the absence of GILT. We will evaluate the role of GILT in Treg cell differentiation of polyclonal T cells and prevention of cutaneous autoimmunity to demonstrate the clinical significance and broad applicability of altered antigen presentation in Treg cell development. We will determine the location where TRP1-specific T cells are required to prevent vitiligo. The impact of these studies is to increase our knowledge of factors that regulate the development and function of skin-specific Treg cells and to determine how alterations in antigen processing affect the development and function of autoreactive Treg cells. In turn, this knowledge has the potential to yield novel targets (such as GILT) to promote Treg cell differentiation and control autoimmunity. Since the effect of GILT is not limited to the presentation of TRP1 or cutaneous autoantigens, modulation of GILT expression or activity may be a broadly applied therapeutic approach for autoimmune disease.

描述（由申请人提供）：调节性T（Treg）细胞在预防皮肤自身免疫和炎症性疾病，如白癜风、牛皮癣、特应性皮炎和系统性红斑狼疮方面发挥着关键作用。 T细胞受体刺激是决定Treg细胞分化的主要因素。因此，减少 T 细胞受体配体的抗原加工途径的操作可用于增强 Treg 细胞发育并减轻自身免疫性疾病。 GILT（γ-干扰素诱导的溶酶体硫醇还原酶）是此类操作的主要候选者，因为 GILT 的缺失会减少 MHC I 类和 II 类抗原的呈递。该项目的长期目标是确定抗原加工途径如何调节皮肤中 T 细胞介导的免疫和自我耐受之间的平衡。 GILT 是抗原呈递细胞溶酶体区室中的一种酶，对于有效处理含有二硫键的抗原至关重要。我们之前的研究表明，GILT 是 MHC II 类限制性酪氨酸酶相关蛋白 1 (TRP1) 呈递所必需的，酪氨酸酶相关蛋白 1 是白癜风和黑色素瘤中的一种临床相关自身抗原。我们开发了 TRP1 特异性 T 细胞受体转基因小鼠模型，其中皮肤特异性 Treg 细胞发育并抑制白癜风。我们假设 GILT 的丧失会增加外周 Treg 细胞的诱导，这些 Treg 细胞归巢于皮肤并控制皮肤自身免疫反应。在当前的提案中，我们将采用一套独特的遗传和免疫学工具，通过研究胸腺内 Treg 细胞发育是否增加、Treg 细胞的外周诱导或 Treg 细胞增殖是否增加，来确定在没有 GILT 的情况下 Treg 细胞增加的病因。在外围。我们将确定在没有 GILT 的情况下导致 Treg 细胞增加的因素。我们将评估 GILT 在多克隆 T 细胞的 Treg 细胞分化和预防皮肤自身免疫中的作用，以证明 Treg 细胞发育中抗原呈递改变的临床意义和广泛适用性。我们将确定需要 TRP1 特异性 T 细胞来预防白癜风的位置。这些研究的影响是增加我们对调节因素的了解皮肤特异性 Treg 细胞的发育和功能，并确定抗原处理的改变如何影响自身反应性 Treg 细胞的发育和功能。反过来，这些知识有可能产生新的靶标（例如 GILT）来促进 Treg 细胞分化和控制自身免疫。由于 GILT 的作用不限于 TRP1 或皮肤自身抗原的呈递，因此调节 GILT 表达或活性可能是一种广泛应用的自身免疫性疾病的治疗方法。