T Cell costimulation: Induction and Regulation of Autoimmunity

项目总结/摘要 Th 17细胞的临床相关性最近通过抗IL-17抗体在治疗中的显著功效而得到强调。 治疗牛皮癣、强直性脊柱炎和多发性硬化症。并非所有的Th 17细胞都是致病性的，并且在某些情况下， 自身免疫性疾病（例如，IBD），抗IL-17抗体使疾病恶化，突出了 选择性靶向致病性但备用的保护性Th 17细胞。共刺激受体及其配体具有 通过调节致病性（Th 1和Th 17）之间的平衡对自身免疫性疾病产生深远影响 和保护性（Treg）细胞类型。抑制分子在Th 17细胞致病性中的作用尚未完全阐明， 探讨了使用时间全基因组转录方法，我们已经确定了模块， 或负调节Th 17细胞发育以及代表Th 17细胞的信号， 自身免疫（致病性）和那些不能（非致病性）。在这些分子中， 分子PROCR（蛋白C受体）在非致病性Th 17细胞上选择性富集。 类似于众所周知的抑制分子PD-1，PROCR可以促进Th 17细胞分化，但一旦 表达抑制Th 17细胞的效应子功能。我们假设PROCR和PD-1可以影响 产生致病性Th 17细胞，从而调节自身免疫性疾病的发展。我们提出 这些具体的目的是解决这一假设：1：研究PD-1和PROCR如何调节诱导， Th 17细胞的功能。由于PD-1和PROCR都是共抑制受体，我们提出， 它们不仅抑制Th 17细胞，而且促进非致病性Th 17细胞的分化。使用PD-1-/- 和PROCRd/d小鼠，我们将分析这两种分子是否协同作用影响Th 17发育， 功能以及它们是否调节异位淋巴滤泡的发育，这是Th 17诱导的 慢性自身免疫2：确定PROCR和PD-1的配体在限制Th 17细胞中的作用 致病性活化蛋白C（aPC）是PROCR的已知配体之一，具有抗凝血和抗肿瘤活性。 抗炎作用。我们已经获得了许多具有选定功能的aPC突变体， 开始测试它们将致病性Th 17细胞转化为非致病性Th 17细胞的能力， 与PD-1配体协同作用以抑制Th 17细胞致病性并改变建立的 自身免疫性疾病3：重建动态监管网络，以确定 PD-1和PROCR控制Th 17细胞的发育和效应子功能。由于我们建立了一个 控制Th 17细胞发育的转录网络，我们处于一个独特的位置，研究如何损失 PD-1和PROCR的相互作用将影响Th 17细胞分化和效应物输出的网络。我们将研究如何 PD-1和PROCR通路中关键节点的扰动可能改变Th 17细胞的命运，并测试它们的免疫应答。 使用EAE模型的相关性。

PROJECT SUMMARY / ABSTRACT The clinical relevance of Th17 cells is recently highlighted by the remarkable efficacy of anti-IL-17 antibodies in treating Psoriasis, Ankylosing spondylitis and Multiple sclerosis. Not all Th17 cells are pathogenic and in some autoimmune diseases (eg. IBD), anti-IL-17 antibodies made disease worse, highlighting the importance of selectively targeting pathogenic but spare protective Th17 cells. Costimulatory receptors and their ligands have a profound impact on autoimmune diseases by regulating the balance between pathogenic (Th1 and Th17) and protective (Treg) cell types. The role of inhibitory molecules in Th17 cell pathogenicity has not been fully explored. Using a temporal whole genome transcriptional approach, we have identified modules that positively or negatively regulate Th17 cell development as well as a signature that represents Th17 cells that can induce autoimmunity (pathogenic) and those that cannot (non-pathogenic). Among these molecules, a novel inhibitory molecule, PROCR (Protein C Receptor), emerged as selectively enriched on non-pathogenic Th17 cells. Similar to the well-known inhibitory molecule PD-1, PROCR can promote Th17 cell differentiation but once expressed inhibit effector functions of Th17 cells. We hypothesize that PROCR and PD-1 can influence the generation of pathogenic Th17 cells and thus regulate the development of autoimmune diseases. We propose these specific aims to address this hypothesis: 1: Study how PD-1 and PROCR regulate induction and effector functions of Th17 cells. Since both PD-1 and PROCR are co-inhibitory receptors, we propose that they do not only inhibit Th17 cells but also promote differentiation of non-pathogenic Th17 cells. Using PD-1-/- and PROCRd/d mice, we will analyze whether the two molecules synergize to affect Th17 development, function and whether they regulate the development of ectopic lymphoid follicles, a hallmark of Th17-induced chronic autoimmunity. 2: Determine the role of ligands of PROCR and PD-1 in limiting Th17 cell pathogenicity. Activated protein C (aPC), one of the known ligands for PROCR, has both anti-coagulant and anti-inflammatory effects. We have obtained a number of aPC mutants with selected functions and are beginning to test their ability to convert pathogenic Th17 cells into non-pathogenic Th17 cells and whether they synergize with PD-1 ligands to inhibit Th17 cell pathogenicity and alter clinical course of established autoimmune diseases. 3: Reconstruct the dynamic regulatory network to define the pathways by which PD-1 and PROCR control development and effector functions of Th17 cells. Since we have built a transcriptional network that controls development of Th17 cells, we are in a unique position to study how loss of PD-1 and PROCR will affect the network of Th17 cell differentiation and effector output. We will study how perturbation of key nodes in the PD-1 and PROCR pathway may change the Th17 cell fate and test their relevance using the EAE model.