Impact of co-inhibitory receptors on Th17 differentiation and pathogenicity

共抑制受体对 Th17 分化和致病性的影响

• 批准号: 277843602
• 负责人: Dr. Markus Schramm
• 金额: --
• 依托单位: Ann Romney Center for Neurologic Diseases
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/277843602?language=en
• 关键词: Impact; co; inhibitory; receptors; Th17

Interleukin-17 producing T helper cells (Th17) cells are linked to the pathogenesis of highly prevalent inflammatory diseases like multiple sclerosis (MS) and rheumatoid arthritis (RA). Anti-IL-17 antibody therapy has shown promising results in the treatment of several autoimmune diseases, but it also worsened disease outcome e.g. in intestinal bowel diseases. Recent discoveries imply that this observed dichotomy is caused due to two different subtypes of Th17 cells, one that induces autoimmunity (pathogenic) and one that does not (non-pathogenic). How these two Th17 phenotypes are regulated in detail is not known, neither is the role of inhibitory molecules in Th17 cell pathogenicity. Previous work suggests that Protein C Receptor (PROCR), which is selectively enriched on non-pathogenic Th17 cells, and programmed cell death protein 1 (PD-1) promote Th17 cell differentiation, but once expressed inhibit effector functions of Th17 cells. This research project addresses the question how these inhibitory molecules regulate Th17 induction and functions. It will be analyzed whether they do not only inhibit pathogenic Th17 cells but also promote differentiation of non-pathogenic Th17 cells. Using PROCR hypomorphic mutant mice and PD-1 knockout mice it will be studied whether PROCR and PD-1 do synergize when controlling effector functions of Th17 cells. Whether changes to the pathogenic signature of Th17 cells induced by PROCR or PD-1 also translate into altered pathogenicity in vivo will be tested using experimental autoimmune encephalomyelitis (EAE), the most common animal model of MS. Several mutants of the PROCR ligand, activated protein C (aPC), which have selective anti-coagulant and/or anti-inflammatory effects, will be tested regarding their effect on Th17 differentiation and their ability to convert pathogenic Th17 cells into non-pathogenic Th17 cells. It will be examined whether aPC can thereby alter the clinical course of EAE. This project will therefore give crucial insights on differentiation and regulation of pathogenic and non-pathogenic Th17 phenotypes and will help to identify specific targets to selectively inhibit pathogenic but spare protective Th17 cells.

产生白细胞介素-17的辅助性T细胞（Th17）细胞与多发性硬化症（MS）和类风湿性关节炎（RA）等高度流行的炎症性疾病的发病机制有关。抗il -17抗体疗法在治疗多种自身免疫性疾病方面显示出良好的效果，但它也会恶化疾病的预后，例如在肠道疾病中。最近的发现表明，这种观察到的二分法是由两种不同的Th17细胞亚型引起的，一种诱导自身免疫（致病性），另一种不诱导自身免疫（非致病性）。这两种Th17表型是如何被详细调控的尚不清楚，抑制分子在Th17细胞致病性中的作用也不清楚。先前的研究表明，在非致病性Th17细胞上选择性富集的蛋白C受体（PROCR）和程序性细胞死亡蛋白1 （PD-1）促进Th17细胞分化，但一旦表达则抑制Th17细胞的效应功能。本研究项目解决了这些抑制分子如何调节Th17诱导和功能的问题。我们将分析它们是否不仅抑制致病性Th17细胞，而且促进非致病性Th17细胞的分化。利用PROCR半形突变小鼠和PD-1敲除小鼠，研究PROCR和PD-1是否协同控制Th17细胞的效应功能。由PROCR或PD-1诱导的Th17细胞致病特征的改变是否也会转化为体内致病性的改变，将通过实验性自身免疫性脑脊髓炎（EAE）进行测试，EAE是ms最常见的动物模型。PROCR配体的几种突变体，活化蛋白C (aPC)，具有选择性抗凝血和/或抗炎作用。将测试它们对Th17分化的影响以及它们将致病性Th17细胞转化为非致病性Th17细胞的能力。我们将研究aPC是否能因此改变EAE的临床病程。因此，该项目将为致病性和非致病性Th17表型的分化和调控提供重要见解，并将有助于确定选择性抑制致病性但备用保护性Th17细胞的特定靶点。