The role of the innate immune system on Treg reprogramming in human autoimmune di

描述（由申请人提供）：多发性硬化症（MS）和1型糖尿病（T1D）是复杂的遗传性疾病，致病性T细胞自身免疫反应靶向并破坏自身组织。然而，对自身反应的T细胞的存在并不足以导致疾病的发生，因为在健康对照者中可以发现自身反应性T细胞；因此，有各种方法可以控制不想要的反应。其中最重要的机制之一是调节性T细胞（Tregs）的活性，它在胸腺和外周免疫系统中都出现，是暴露于抗原的结果。虽然最初认为treg代表同质的终末期分化群体，但最近的数据表明，treg存在于免疫反应特异性亚群中，与它们控制的Th亚群平行，可以在某些条件下被重新编程以分泌促炎细胞因子。因此，Treg对炎症环境的适应和变色龙样倾向于呈现th样表型是在小鼠模型中观察到的生理和基本属性。我们最近发现MS或T1D患者分泌IFN-？与健康对照相比，提示这种重编程可能也存在于人类中，并且在某些条件下可能参与自身免疫性疾病的发病机制。因此，本提案解决的一个基本问题是“确定自身免疫性疾病中产生Th-Tregs的机制，以及这些细胞在基础、炎症和治疗条件下如何在体内发挥作用”。此外，Treg反应的诱导和有效性受其解剖位置的影响。TGF-¿、IL-6等在Treg稳态中起核心作用的因子在粘膜表面、中枢神经系统和胰腺中表达不同，并可能局部影响Treg分化。因此，在本提案中，我们将解决第二个假设，即“treg的解剖位置和免疫环境决定了它们在人类中的分化途径，而这些过程在容易产生自身免疫的个体中发生了改变。”以下目标代表了两个中心的共同努力，这将使我们能够使用相同的实验和疾病平台来解决这些问题。1. 确定健康个体和MS合并T1D患者th样Treg亚群分化和稳定性的机制。2. 以确定TLR结扎驱动的先天因子是否调控th样Tregs。确定人th样Tregs在体内的功能以及免疫治疗在人和人源化小鼠模型中的效果。这些研究将确定自身免疫中Th-Tregs的广泛和疾病特异性特征，并有望确定对预防MS， T1D和潜在的其他自身免疫性疾病重要的新机制。此外，这些研究可以确定可能被现有或新的免疫疗法靶向的途径。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) and type 1 diabetes (T1D) are complex genetic diseases where pathogenic T cell autoimmune responses target and destroy self-tissue. However, the presence of T cells reactive to self alone is not sufficient for disease o occur as autoreactive T cells can be found in healthy control subjects; thus various means are available that control unwanted responses. One of the most important mechanisms is the activity of regulatory T cells (Tregs), which arise both in thymus and in the peripheral immune system as a consequence of exposure to antigens. While it was originally thought that Tregs represented a homogenous, end-stage differentiated population, recent data suggest that Tregs exist in immune response-specific subsets, which parallel the Th subsets that they control, can under certain conditions, be reprogrammed to secrete pro-inflammatory cytokines. Thus, Treg adaptation to the inflammatory milieu and chameleon-like propensity to take on Th-like phenotypes is physiologic and a fundamental attribute observed in mouse models. We have recently found that there is an increased frequency of Tregs from MS or T1D patients that secrete IFN-? compared to healthy controls, suggesting that this reprogramming may be present in humans as well and under certain conditions can be involved in the pathogenesis of autoimmune diseases. Thus, one fundamental question, addressed in this proposal is "to determine the mechanisms that generate Th-Tregs in autoimmune diseases and how these cells function in vivo under basal, inflammatory and therapeutic conditions." In addition, the induction and effectiveness of Treg responses are affected by their anatomic location. Factors that have central roles in Treg homeostasis such as TGF-¿, IL-6 and others, are expressed differently at mucosal surfaces, in the CNS, and in the pancreas, and may affect Treg differentiation locally. Thus, in this proposal we will address a second hypothesize that "the anatomic location and immune environment of Tregs dictates their pathway of differentiation in humans and that these processes are altered in individuals prone to autoimmunity." The following aims represent a concerted effort between two centers that will allow us to address these questions using the same experimental and disease platforms. 1. To determine what mechanisms are involved in the differentiation and stability of Th-like Treg subsets in healthy individuals and patients with MS and T1D. 2. To determine whether innate factors, driven by TLR ligation modulate Th-like Tregs. 3. To determine the function of human Th-like Tregs in vivo and the effects of immune therapies in humans and humanized mouse models. These studies will identify wide-ranging and disease-specific features of Th-Tregs in autoimmunity, and, hopefully, identify novel mechanisms that are important for prevention of MS, T1D, and potentially other autoimmune diseases. In addition, these studies may identify pathways that may be targeted by existing or novel immune therapeutics. PUBLIC HEALTH RELEVANCE: Multiple sclerosis (MS) and type 1 diabetes (T1D) are complex genetic diseases where pathogenic T cell autoimmune responses target and destroy self-tissue. It is now believed that defects in a population of cells with immunosuppressive properties called "regulatory T cells" are central to the development of autoimmune diseases, but many facets of the biology of these cells in humans are still unknown. In this project, we will pursue efforts to determine how these cells are generated in health and disease and identify key molecules that could be targeted therapeutically to restore normal processes in MS and T1D.