GILT and regulation of Treg development in cutaneous autoimmunity

描述(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方面发挥关键作用，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，操纵抗原处理途径，减少T细胞受体配体，可能被用来促进Treg细胞的发育，减少自身免疫性疾病。GILT(伽马干扰素诱导的溶酶体硫醇还原酶)是这种操作的首选候选方法，因为GILT的丢失会减少MHC I和II类抗原的呈递。该项目的长期目标是确定抗原处理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是抗原提呈细胞溶酶体隔室中的一种酶，对有效处理含有二硫键的抗原至关重要。我们先前的研究表明，对于MHC II类限制性酪氨酸酶相关蛋白1(TRP1)的呈递，GILT是必需的，TRP1是白癜风和黑色素瘤的临床相关自身抗原。我们已经建立了一种TRP1特异性T细胞受体转基因小鼠模型，在该模型中，皮肤特异性Treg细胞可以发展和抑制白癜风。我们假设，镀金的丧失增加了外周诱导的Treg细胞，这些细胞定位于皮肤并控制皮肤自身免疫反应。在目前的方案中，我们将使用一套独特的遗传和免疫学工具来确定在没有GILT的情况下Treg细胞增加的病因，方法是调查胸腺内Treg细胞的发育增加、Treg细胞的外周诱导或外周Treg细胞的增殖。我们将确定在没有GILT的情况下，LAD导致Treg细胞增加的因素。我们将评估GILT在多克隆T细胞向Treg细胞分化和预防皮肤自身免疫中的作用，以展示抗原提呈改变在Treg细胞发育中的临床意义和广泛适用性。我们将确定预防白癜风所需的TRP1特异性T细胞的位置。这些研究的影响是增加我们对调控因素的了解 研究皮肤特异性Treg细胞的发育和功能，并确定抗原处理过程中的变化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点(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的表达或活性可能是一种广泛应用于自身免疫性疾病的治疗方法。

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.