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

描述（由申请人提供）：IL-17（IL-17 A）是相对较新的CD 4 + T辅助细胞亚群（称为“Th 17”细胞）的标志性细胞因子。IL-17和Th 17细胞在银屑病、RA、SLE和其他自身免疫性疾病中升高。因此，Th 17细胞已经成为自身免疫病理学的主要贡献者，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银屑病和类风湿性关节炎（RA）的临床试验中显示出希望，并且正在其他条件下进行评估。相反，IL-17是对细胞外微生物免疫的重要介质。最近的工作特别涉及IL-17对真菌如白色念珠菌的免疫。IL-17还在对肠道微生物群的反应中起作用，其中异常活性促进全身性炎症。来自肠道植物群的信号有助于免疫稳态，但也有助于自身免疫，其通过Th 17/IL-17轴相互连接。虽然许多研究工作集中在Th 17的产生和功能，IL-17介导下游信号的机制受到的关注要少得多。IL-17受体属于采用新的信号传导机制的独特细胞因子受体家族。一个新兴的主题是，有许多机制的地方，以限制IL-17和Th 17的活动，这些负调控途径的缺陷有助于自身免疫和免疫病理学。该资助的第一个资助期专注于IL-17 R与下游信号转导途径的结构-功能关系。在第一个资助周期的工作中，我们发现了2种以前从未与IL-17通路相关的新信号传导抑制剂。一种是去泛素化酶，似乎靶向NF-κ B通路。另一个是一个更少理解的信号中间体，具有多种活动。敲除任何一种都会导致不受控制的全身性炎症，部分由肠道微生物群的信号介导。我们假设不受限制的IL-17信号传导也有助于潜在的炎症。本申请的目的是详细了解IL-17受体信号传导是如何被抑制的，以及其抑制的生物学后果，无论是关于基线炎症还是对白色念珠菌的免疫力。这些发现将最终提供可用于增强、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.