Role of Innate Lymphoid Cells in Autoimmunity

描述(申请人提供)：1型糖尿病(T1D)是一种自身免疫性疾病，导致胰岛分泌胰岛素的β细胞被破坏。T1D主要由自身反应性T细胞驱动，但也涉及天然免疫系统的组成部分，包括单核细胞、树突状细胞和自然杀伤(NK)细胞。自然杀伤细胞(NK细胞)属于天然淋巴样细胞(ILC)家族，存在于具有淋巴形态和其他特性的天然细胞中。最近定义了新的ILC群体，ILC现在被细分为三个主要类别：ILc1细胞(NK细胞)；ILC2细胞(产生IL-13和IL-5的GATA-3+先天辅助细胞)和ILC3细胞(RORγt+ILCs，包括产生IL-22和/或IL-17的ILCs的不同亚群)。从功能上讲，ILC2s和ILC3s参与了对感染的保护性免疫，但它们也可以根据情况诱导或控制慢性炎症。重要的是，ILCs在自身免疫中的作用在很大程度上是未知的。因此，在这项建议中，我们将解决ILC人群在自身免疫性糖尿病的发展和进展中发挥关键作用的总体假设。我们将利用创新的小鼠模型，包括报告鼠，允许选择性地识别和删除RoRγt+ILC3和产生IL-5/13的ILC2细胞。最重要的是，我们观察到ILCs是在T1D易感的非肥胖糖尿病(NOD)小鼠的胰腺中发现的第一个细胞，这表明在疾病的发生中可能起到了作用。最后，我们将解决另一个关键假说，即存在于包括胰腺在内的组织中的ILC2细胞，与旨在促进调节性T细胞(Treg)的IL-2疗法的负面副作用密切相关。最近在新发的T1D患者中测试IL-2治疗的安全性的研究证实了小鼠实验证明Tregs的数量增加。然而，在某些情况下，这种治疗导致了一过性β细胞功能障碍、Th17细胞增加和嗜酸性粒细胞增多。重要的是，我们的初步研究表明，NOD小鼠胰腺中存在的ILC2对IL-2治疗有反应，可能是这些有害影响的原因之一。在这份R21修订的申请中，我们提出了以下具体目标来解决这些假设。1)研究NOD小鼠ILC2和ILC3亚群的特征；2)确定ILC2在自身免疫性糖尿病发生和调节中的功能作用；3)检测IL-2治疗对ILC2的影响以及ILC2在IL-2治疗的生物学和临床效应中的作用。这些研究将表征糖尿病期间胰腺中新的ILC亚群，并确定它们对疾病的影响。据我们所知，这将是自身免疫性糖尿病中ILC2和RoRγt+ILC3的第一个特征。我们的研究结果可能会将目前的T1D教条从以T细胞为中心的范例转变为包括ILC参与的范例。此外，我们的研究可能具有重要的临床意义，通过识别T1D的新治疗靶点，并允许更好地预测针对ILC和T细胞共同途径的治疗的“非靶点”效果。

DESCRIPTION (provided by applicant): Type 1 Diabetes (T1D) is an autoimmune disease resulting in the destruction of pancreatic islet insulin- producing beta cells. T1D is mainly drive by autoreactive T cells but components of the innate immune system have been implicated as well, including monocytes, dendritic cells and natural killer (NK) cells. NK cells belong to the innate lymphoid cell (ILC) family, which consists in innate cells that share a lymphoid morphology and other properties. Novel populations of ILCs have been defined recently and ILCs are now subdivided in three main categories: ILC1 cells (NK cells); ILC2 cells (IL-13- and IL-5-producing GATA-3+ innate helper cells, and ILC3 cells (RORγt+ ILCs, which include distinct subsets of IL-22- and/or IL-17-producing ILCs). Functionally, ILC2s and ILC3s are involved in protective immunity against infections but they can also induce or control chronic inflammation depending on the circumstances. Importantly, the role of ILCs in autoimmunity is largely unknown. Thus, in this proposal we will address the overall hypothesis that ILC populations play a critical role in the development and progression of autoimmune diabetes. We will take advantage of innovative mouse models that include reporter mice allowing the identification and deletion of RORγt+ ILC3s and IL-5/13-producing ILC2 cells selectively. Most significantly, we observe that ILCs are the first cells found in the pancreas of T1D-susceptible non-obese diabetic (NOD) mice suggesting a potential role in disease initiation. Finally, we will address another key hypothesis, namely, that ILC2 cells, present in tissues, including the pancreas, are critically involved in the negative side effects of IL-2 therapies designed to promote regulatory T cells (Tregs). Recent studies to test the safety of IL-2 therapy in new-onset T1D patients have validated mouse work demonstrating increased numbers of Tregs..However, in some instances, the treatment resulted in transient β cell dysfunction, increased Th17 cells and eosinophilia. Importantly, our preliminary studies suggest that ILC2s present in the pancreas of NOD mice respond to IL-2 treatment and may be responsible for some of these unwanted effects. In this R21 Revised application we propose the following specific aims to address these hypotheses. 1) To characterize the ILC2 and ILC3 subsets in the NOD mouse; 2) To determine the functional effect of ILC2s on the development and regulation of autoimmune diabetes; and 3) To examine the effect of IL-2 therapy on ILC2s and the role of ILC2s in the biological and clinical effect of IL-2 therapy. These studies will characterize novel ILC subsets i the pancreas during diabetes and identify their influence on disease. To our knowledge, this will be the first characterization of ILC2s and RORγt+ ILC3s in autoimmune diabetes. The results of our study may shift the current T1D dogma from a T cell-centric paradigm to one that includes an involvement of ILCs. Additionally, our studies could have important clinical implications by identifying novel therapeutic targets in T1D and allowing better a prediction of "off-target" effecs of therapy directed at pathways shared by ILCs and T cells.