Developing eTACs as a novel method of tolerance in Type 1 Diabetes

描述（由申请人提供）：免疫系统受到多层调节，这些调节促进对自身的耐受性，并且对于预防自身免疫性疾病（如1型糖尿病）至关重要。维持免疫耐受的一个关键因素是自身免疫调节因子（Aire）基因。Aire被鉴定为人类自身免疫综合征（Autoimmune Polyglandular Syndrome Type 1）中的缺陷基因，突出了该基因在耐受性中的关键重要性。Aire在特化的胸腺髓质上皮细胞（mTEC）中起作用，以促进数百种自身抗原的表达，目的是去除发育中的自身反应性T细胞，这一过程称为阴性选择。最近，我们已经描述了一个额外的网站Aire的行动中发现的一个独特的群体的抗原呈递细胞在外周淋巴器官，我们称之为胸腺外Aire表达细胞（eTAC）。与mTEC一样，Aire在eTAC中起作用，以促进许多自身抗原的表达，这些抗原与胸腺中Aire控制的抗原不同，这表明eTAC在促进外周耐受性方面具有互补作用。事实上，eTAC能够将自身抗原呈递给外周T细胞以引起自身反应性细胞的缺失或功能失活，从而防止自身免疫。关于这种新的细胞类型仍有很多未知之处;然而，eTAC的骨髓起源的发现为这种细胞类型的扩增和操纵开辟了潜力，用于促进自身耐受性的治疗应用。我们已经开发了一套强大的遗传工具，使我们能够定义这些细胞的生长和发育，并通过与其他类型的抗原呈递细胞进行比较，确定外周耐受诱导的潜在独特途径。我们假设eTAC代表了一种独特的致耐受性APC群体，在介导外周耐受中具有重要作用，并可作为诱导耐受的新治疗靶点。因此，我们的具体目标是：（1）定义和表征eTAC的谱系和生长要求，（2）定义eTAC作用的位点和机制，以及（3）确定eTAC功能的丧失和获得如何调节T1 D模型中的疾病。总之，我们的研究将有助于确定eTAC的起源，它们增强耐受性的机制，以及我们如何利用它们预防1型糖尿病和其他自身免疫性疾病。

DESCRIPTION (provided by applicant): The immune system is subject to multiple layers of regulation that promote tolerance to self and that are critical for the prevention of autoimmune diseases, such as Type 1 diabetes. A key player in the maintenance of immune tolerance is the Autoimmune Regulator (Aire) gene. Aire was identified as the defective gene in the human autoimmune syndrome Autoimmune Polyglandular Syndrome Type 1, highlighting the critical importance of this gene in tolerance. Aire acts within specialized medullary thymic epithelial cells (mTECs) to promote the expression of hundreds of self-antigens for the purpose of removing developing self-reactive T cells, a process known as negative selection. Recently, we have described an additional site of Aire action within a unique population of antigen-presenting cells found in peripheral lymphoid organs that we have termed extra-thymic Aire-expressing cells (eTACs). As in mTECs, Aire acts in eTACs to promote the expression of many self-antigens that are distinct from those controlled by Aire in the thymus, suggesting a complementary role of eTACs in promoting tolerance in the periphery. Indeed, eTACs are capable of presenting self-antigens to peripheral T cells to cause deletion or functional inactivation of the self-reactive cells, thus preventing autoimmunity. Much remains unknown about this novel cell type; however, the discovery of the bone-marrow origins of eTACs opens up the potential for expansion and manipulation of this cell type for therapeutic applications in promoting self-tolerance. We have developed a powerful set of genetic tools that will allow us to define the growth and development of these cells as well as identify potentially unique pathways of peripheral tolerance induction, through comparisons with other types of antigen-presenting cells. We hypothesize that eTACs represent a unique tolerogenic population of APCs with an important role in mediating peripheral tolerance and can serve as a novel therapeutic target for tolerance induction. Therefore, our specific aims are: (1) to define and characterize the lineage and growth requirements of eTACs, (2) to define the sites and mechanisms of eTAC action, and (3) to determine how loss and gain of function in eTACs can modulate disease in models of T1D. Taken together, our studies will help determine origins of eTACs, the mechanisms by which they enforce tolerance, and how we may employ them in the prevention of Type 1 diabetes and other autoimmune diseases.