Negative Control of IL-17R Signaling: Implications for Fungal Immunity

描述(申请人提供)：IL-17(IL-17A)是一种相对较新的CD4+T辅助细胞亚群的标志性细胞因子，称为“Th17”细胞。IL-17和Th17细胞在银屑病、类风湿性关节炎、系统性红斑狼疮等自身免疫性疾病中升高。因此，Th17细胞已经成为自身免疫病理的主要贡献者，这已经转化为令人兴奋的治疗干预途径。最值得注意的是，针对IL-17或其受体的抗体已在牛皮癣和类风湿性关节炎(RA)的临床试验中显示出希望，并正在其他条件下进行评估。相反，IL-17是细胞外微生物免疫的重要介质。最近的研究特别指出，IL-17与白念珠菌等真菌的免疫有关。IL-17也在对共生微生物区系的反应中发挥作用，在微生物区系中，异常活动促进全身炎症。来自肠道菌群的信号有助于免疫动态平衡，也有助于自身免疫，两者通过Th17/IL-17轴相互联系。虽然许多研究都集中在Th17的产生和功能上，但IL-17介导下游信号的机制却受到的关注要少得多。IL-17受体属于一个独特的细胞因子受体家族，它使用新的信号机制。一个新的主题是，有许多机制存在，以限制IL-17和Th17的活性，而这些负调控途径的缺陷有助于自身免疫和免疫病理学。这笔赠款的第一个资助期侧重于IL-17R与下游信号转导途径之间的结构-功能关系。在第一个授予周期的工作中，我们确定了两个以前从未与IL-17途径相关的新信号抑制物。一种是去泛素酶，它似乎针对的是核因子-kappaB途径。另一种是一种更难理解的具有多个活动的信号中间体。其中任何一种的敲除都会导致不受控制的全身炎症，部分是由肠道微生物区系的信号介导的。我们假设，不受限制的IL-17信号也参与了潜在的炎症。这项应用的目的是详细了解IL-17受体信号是如何被抑制的，以及其抑制的生物学后果，既与基线炎症有关，也与对白色念珠菌的免疫有关。这些发现最终将提供可用于加强、预测、诊断和/或治疗IL-17介导的炎症的信息。

DESCRIPTION (provided by applicant): IL-17 (IL-17A) is the signature cytokine of a relatively new CD4+ T helper subset, known as "Th17" cells. IL-17 and Th17 cells are elevated in psoriasis, RA, SLE and other autoimmune diseases. Accordingly, Th17 cells have emerged as a major contributor to autoimmune pathology, which has translated into exciting avenues of therapeutic intervention. Most notably, antibodies against IL-17 or its receptor have shown promise in clinical trials for psoriasis and rheumatoid arthritis (RA), and are being evaluated in other conditions as well. Conversely, IL-17 is an essential mediator of immunity to extracellular microbes. Recent work has especially implicated IL-17 in immunity to fungi such as Candida albicans. IL-17 also plays a role in responses to commensal microbiota, where aberrant activity promotes systemic inflammation. Signals from intestinal flora contribute to immune homeostasis but also to autoimmunity, which are interconnected through the Th17/IL-17 axis. Although much research effort has focused on Th17 generation and function, the mechanisms by which IL-17 mediates downstream signals have received far less attention. The IL-17 receptor belongs to a unique cytokine receptor family that employs novel mechanisms of signaling. An emerging theme is that there are numerous mechanisms in place to constrain IL-17 and Th17 activity, and defects in these negative regulatory pathways contribute to autoimmunity and immunopathology. The first funding period of this grant focused on structure-function relationships in IL-17R with respect to downstream signal transduction pathways. In work during the first grant cycle, we identified 2 new signaling inhibitors never previously connected to the IL-17 pathway. One is a deubiquitinating enzyme that appears to target the NF-kappaB pathway. The other is a more poorly-understood signaling intermediate with multiple activities. Knockouts of either lead to uncontrolled systemic inflammation, mediated in part by signals from intestinal microbiota. We hypothesize that unrestrained IL-17 signaling also contributes to the underlying inflammation. The goal of this application is to understand in detail how IL-17 receptor signaling is inhibited, and the biological consequences of its inhibition, both with respect to baseline inflammation but also immunity to Candida albicans. These findings will ultimately provide information that may be used to enhance, predict, diagnose and/or treat IL-17-mediated inflammation.