T Cell costimulation: Induction and Regulation of Autoimmunity

T 细胞共刺激：自身免疫的诱导和调节

• 批准号: 8742093
• 负责人: VIJAY K. KUCHROO
• 金额: $ 52.53万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8742093
• 关键词: Address; Affect; Animal Model; Ankylosing spondylitis; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Applications Grants; Area; Autoimmune Diseases; Autoimmunity; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Central Nervous System Diseases; Chronic; Clinical; Coagulants; Data; Defect; Demyelinations; Development; Disease; Elements; Equilibrium; Experimental Autoimmune Encephalomyelitis; Functional disorder; Generations; Genome; Grant; Human; Individual; Inflammation; Interferons; Interleukin-17; Ligands; Lymphoid Follicle; Modeling; Multiple Sclerosis; Mus; Myelin; Output; Pathogenicity; Pathway interactions; Phenotype; Positioning Attribute; Protein C; Psoriasis; Regulation; Regulatory T-Lymphocyte; Role; Site; T-Lymphocyte; Testing; Tissues; Virus Diseases; activated Protein C; base; cell type; chronic graft versus host disease; clinically relevant; exhaust; exhaustion; genetic linkage; mutant; novel; receptor; receptor function; receptor upregulation; response; tool

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.

项目摘要 /摘要 最近，抗IL-17抗体在 治疗牛皮癣，强直性脊柱炎和多发性硬化症。并非所有Th17细胞都是致病性的，在某些细胞中 自身免疫性疾病（例如IBD），抗IL-17抗体使疾病恶化，强调了重要性 有选择地靶向致病性但备用保护性TH17细胞。共刺激受体及其配体具有 通过调节致病性之间的平衡对自身免疫性疾病产生深远影响（TH1和TH17） 和保护性（Treg）细胞类型。抑制分子在Th17细胞致病性中的作用尚未完全 探索。使用时间整体基因组转录方法，我们已经确定了积极的模块 或负调节Th17细胞发育以及代表可以诱导的Th17细胞的特征 自身免疫性（致病性）和无法（非致病性）的自身免疫性。在这些分子中，一种新颖的抑制作用 分子，Procr（蛋白质C受体）有选择地富含非致病性TH17细胞。 与众所周知的抑制性分子PD-1相似，PROCR可以促进Th17细胞分化，但一次 表达抑制Th17细胞的效应功能。我们假设PROCR和PD-1可以影响 致病性Th17细胞的产生，从而调节自身免疫性疾病的发展。我们建议 这些具体目的是解决这一假设：1：研究PD-1和PROCR如何调节归纳和 Th17细胞的效应函数。由于PD-1和PROCR都是共同抑制性受体，因此我们建议 它们不仅抑制Th17细胞，而且促进了非致病性TH17细胞的分化。使用PD-1 - / - 和procrd/d小鼠，我们将分析两个分子是否协同影响Th17的发展， 功能以及它们是否调节异位淋巴卵泡的发展，这是Th17诱导的标志 慢性自身免疫。 2：确定PROCR和PD-1配体在限制Th17细胞中的作用 致病性。活化的蛋白C（APC）是PRCR的已知配体之一，既有抗凝蛋白，又具有 抗炎作用。我们已经获得了许多具有选定功能的APC突变体，并且 开始测试他们将病原性TH17细胞转化为非致病TH17细胞的能力，以及它们是否 与PD-1配体协同抑制Th17细胞致病性并改变已建立的临床过程 自身免疫性疾病。 3：重建动态调节网络以定义途径 PD-1和PROCR控制Th17细胞的开发和效应子功能。由于我们已经建立了 控制Th17细胞开发的转录网络，我们处于独特的位置，可以研究损失 PD-1和PROCR的网络将影响Th17细胞分化和效应子输出的网络。我们将研究如何 PD-1和PROCR途径中关键节点的扰动可能会改变Th17细胞命运并测试其 使用EAE模型的相关性。