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性和炎症性疾病中起关键作用，例如白癜风，牛皮癣，特应性皮肤炎和全身性狼疮。 T细胞受体刺激是决定Treg细胞分化的主要因素。因此，可以使用减少T细胞受体配体的抗原加工途径来增强Treg细胞发育并减少自身免疫性疾病。 GILT（伽马 - 互化诱导的溶酶体还原酶）是进行这种操纵的主要候选者，因为镀金的损失减少了MHC I类和II类抗原子集的呈现。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性之间的平衡。镀金是抗原呈现细胞的溶酶体区室中的一种酶，这对于有效加工含有二硫键的抗原至关重要。我们先前的研究表明，MHC II类限制性蛋白相关蛋白1（TRP1）（一种与临床上与白癜风和黑色素瘤相关的自身抗原）所必需的镀金。我们已经开发了一种TRP1特异性T细胞受体转基因小鼠模型，其中皮肤特异性Treg细胞会发育并抑制白紫色。我们假设镀金的损失会增加归入皮肤的Treg细胞的周围诱导并控制皮肤自身免疫性反应。在当前的提案中，我们将采用一组独特的遗传和免疫学工具来确定在没有镀金的情况下增加Treg细胞增加的病因，通过研究是否增加了内膜内的Treg细胞发育，Treg细胞的周围诱导或周围Treg细胞的增殖。我们将在没有镀金的情况下确定LAD增加Treg细胞的因素。我们将评估GILT在多克隆T细胞的Treg细胞分化中的作用，并预防皮肤自身免疫性，以证明临床意义和广泛的抗原表现呈递在Treg细胞发育中的影响。我们将确定需要TRP1特异性T细胞以防止白癜风的位置。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，并确定抗原加工的变化如何影响自动反应性Treg细胞的发育和功能。反过来，这种知识有可能产生新的靶标（例如镀金）来促进Treg细胞分化和控制自身免疫性。由于镀金的效果不仅限于TRP1或皮肤自身抗原的呈现，因此镀金表达或活性的调节可能是一种广泛应用的自身免疫性疾病的治疗方法。