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

说明(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，对预防自身免疫性疾病至关重要，如1型糖尿病。自身免疫调节因子(Aire)基因在维持免疫耐受中起关键作用。AIRE基因被确定为人类自身免疫综合征自身免疫性多腺体综合征1型的缺陷基因，突显了该基因在耐受中的关键重要性。AIRE在特化的髓质胸腺上皮细胞(MTECs)内发挥作用，促进数百种自身抗原的表达，以消除正在发育的自我反应性T细胞，这一过程被称为负选择。最近，我们描述了在外周淋巴器官中发现的一组独特的抗原提呈细胞中的一个额外的Aire作用部位，我们称之为胸腺外Aire表达细胞(ETACs)。与在mTEC中一样，eTACs中的Aire作用于促进胸腺中许多不同于Aire控制的自身抗原的表达，这表明eTACs在促进外周耐受方面具有互补作用。事实上，eTAC能够将自身抗原递送到外周T细胞，导致自身反应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许多未知之处；然而，eTAC的骨髓起源的发现为这种细胞类型的扩增和操纵在促进自我耐受方面的治疗应用打开了可能性。我们已经开发了一套强大的遗传工具，通过与其他类型的抗原提呈细胞进行比较，我们可以定义这些细胞的生长和发育，并识别潜在的独特的外周耐受诱导途径。我们假设eTAC代表了一个独特的耐受性APC群体，在调节外周耐受中起着重要作用，并可作为诱导耐受的新的治疗靶点。因此，我们的具体目标是：(1)定义和表征eTAC的谱系和生长需求，(2)定义eTAC的作用部位和机制，以及(3)确定eTAC功能的丧失和获得如何在T1D模型中调节疾病。综上所述，我们的研究将有助于确定eTAC的起源，它们增强耐受的机制，以及我们如何将它们用于预防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.