GILT and regulation of Treg development in cutaneous autoimmunity

GILT 和皮肤自身免疫中 Treg 发育的调节

• 批准号: 8582162
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582162
• 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; 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; public health relevance; tool

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中发挥关键作用，如白癜风、牛皮癣、特应性皮炎和系统性红斑狼疮。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能用于增强Treg细胞的发育和减轻自身免疫性疾病。GILT （γ -干扰素诱导溶酶体硫醇还原酶）是这种操作的主要候选物，因为GILT的丢失减少了MHC I类和II类抗原亚群的呈现。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隔室中的一种酶，对有效处理含二硫键的抗原至关重要。我们之前的研究表明，GILT是MHC ii类限制性呈递酪氨酸酶相关蛋白1 （TRP1）所必需的，TRP1是白癜风和黑色素瘤的临床相关自身抗原。我们开发了一种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的缺失增加了Treg细胞的外周诱导，Treg细胞是皮肤的家园并控制皮肤自身免疫反应。在目前的建议中，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、外周Treg细胞诱导或外周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。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，以证明改变抗原呈递在Treg细胞发育中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了我们对调节因素的认识