Regulation of adaptive immunity by the NOD-like receptor NLRP10

NOD 样受体 NLRP10 对适应性免疫的调节

基本信息

批准号：
8612109
负责人：
Stephanie Caroline Eisenbarth
金额：
$ 41.63万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8612109
关键词：
Adhesions Affect Allergens Allergic Disease Animal Model Animals Antigens Asthma Automobile Driving Binding CD4 Positive T Lymphocytes CD8B1 gene Cell Adhesion Cell Maturation Cell surface Cell-Matrix Junction Cells Cross Presentation Cross-Priming Cytotoxic T-Lymphocytes Data Defect Dendritic Cells Development Emigrations Engineering Equilibrium Extracellular Matrix Family Goals Helper-Inducer T-Lymphocyte Heparan Sulfate Proteoglycan ITGAM gene Immune Immune response Immunity Immunization Immunologics In Vitro Inflammatory Influenza Integrins Intervention Left Life Ligands Lung Lymph Mediating Modeling Molecular Movement Mus Paralysed Pathway interactions Pattern recognition receptor Pollen Population Proteins Pyroglyphidae Recombinants Regulation Research Role Signal Pathway Structure of parenchyma of lung T cell response T-Cell Activation T-Lymphocyte Testing Th2 Cells Time Tissues Toll-like receptors Viral Viral Antigens Virus Diseases Work adaptive immunity airborne allergen allergic airway inflammation base cell motility cell type chemokine fibroglycan in vivo in vivo Model influenzavirus inhibitor/antagonist lymph nodes member migration novel pathogen public health relevance pulmonary function receptor response trafficking

项目摘要

DESCRIPTION (provided by applicant): The research outlined in the proposal aims to elucidate a fundamental pathway regulating dendritic cell induction of T cell sensitization to allergens in the lung. Work over the past 15 years has determined that mature pulmonary dendritic cells (DC) from the lung regulate type 2 CD4+ T cell (Th2) responses to allergens in asthma and that activation of pattern recognition receptors such as Toll-like receptors (TLRs) is a primary determinant of DC maturation driving sensitization. Although the early steps of TLR-induced DC maturation and the later steps of chemokine guided migration to draining lymph nodes are well characterized, relatively little is known about the intermediate step of DC detachment from inflamed tissues. We recently discovered a new innate immune pathway within the DC that specifically regulates its ability to egress from inflamed tissues while leaving the ret of the inflammatory and antigen presenting functions intact. NLRP10 is a member of the NOD-like receptor class of pattern recognition receptors and in its absence, DCs fail to traffic antige to lymph nodes and consequently CD4+ T cell priming is profoundly impaired. We will delineate how NLRP10 regulates dendritic cell movement, in exactly which type of DC and what aspects of lung immunity are impaired in the absence of NLRP10 through the following two specific aims. Aim 1) Identify NLRP10-dependent and - independent dendritic cell subsets in the lung and define their ability to activate CD4+ and CD8+ T cells. Preliminary data suggests that loss of NLRP10 only affects a subset of DCs (expressing the marker CD11b), which preferentially prime CD4+ but not CD8+ T cells. We hypothesize that paralysis of NLRP10-dependent DCs in the lung will result in tolerance rather than Th2 priming following aeroallergen exposure while leaving NLRP10-independndent DC priming of anti-viral CD8+ T cells intact. We will test this hypothesis in Aim 1 using in vivo aeroallergen sensitization models (Th2) and influenza infection (CD8+ T cell). NLRP10-deficient mice provide the only animal model in which the function of the migratory CD11b+ DC subset is specifically affected and therefore allows for the first time determination of the exact role of these DCs in pulmonary immune responses. Aim 2) Determine whether failed DC trafficking to lymph nodes is due to impaired DC detachment from lung extracellular matrix molecules. To define the molecular interactions regulating DC release from the lung we will develop matrices with recombinant matrix molecules to test NLRP10-deficient DC adhesion and migration in vitro; further we will block primary determinants of DC attachment to the lung parenchyma in vivo to overcome failed Th2 priming to aeroallergens in NLRP10-deficient mice. If loss of NLRP10 selectively abrogates DC-mediated CD4+ T cell priming to aeroallergens, then targeting this pathway might allow us to control the balance between sensitization and tolerance in allergic disease while potentially leaving protective CD8+ T cell immunity intact. Therefore our long-term goal following completion of these studies is to develop a DC-based approach to treat allergic disease through inhibition of NLRP10 pathways.

描述（由申请人提供）：提案中概述的研究旨在阐明调节树突状细胞诱导 T 细胞对肺部过敏原敏感的基本途径。过去 15 年的工作已经确定，来自肺部的成熟肺树突状细胞 (DC) 调节 2 型 CD4+ T 细胞 (Th2) 对哮喘过敏原的反应，并且模式识别受体（例如 Toll 样受体 (TLR)）的激活与DC 成熟驱动敏化的主要决定因素。尽管 TLR 诱导 DC 成熟的早期步骤和趋化因子引导迁移至引流淋巴结的后期步骤已得到很好的表征，但对于 DC 从发炎组织脱离的中间步骤知之甚少。我们最近在树突状细胞内发现了一种新的先天免疫通路，该通路特异性调节其从发炎组织中逸出的能力，同时保持炎症和抗原呈递功能的完整性。 NLRP10 是模式识别受体 NOD 样受体类别的成员，如果没有它，DC 就无法将抗原运输到淋巴结，因此 CD4+ T 细胞启动会严重受损。我们将通过以下两个具体目标来描述NLRP10如何调节树突状细胞的运动、具体是哪种类型的树突状细胞以及在NLRP10缺失的情况下肺免疫的哪些方面受到损害。目标 1) 鉴定肺中 NLRP10 依赖性和非依赖性树突状细胞亚群，并确定它们激活 CD4+ 和 CD8+ T 细胞的能力。初步数据表明，NLRP10 的缺失仅影响 DC 的子集（表达标记 CD11b），它们优先启动 CD4+ T 细胞，而不是 CD8+ T 细胞。我们假设，在接触空气过敏原后，肺中 NLRP10 依赖性 DC 的麻痹将导致耐受性而不是 Th2 启动，同时使抗病毒 CD8+ T 细胞的 NLRP10 独立 DC 启动保持完整。我们将使用体内空气过敏原致敏模型 (Th2) 和流感感染（CD8+ T 细胞）在目标 1 中测试这一假设。 NLRP10 缺陷小鼠提供了唯一一种迁移性 CD11b+ DC 子集的功能受到特别影响的动物模型，因此首次可以确定这些 DC 在肺部免疫反应中的确切作用。目标 2) 确定 DC 向淋巴结运输失败是否是由于 DC 与肺细胞外基质分子的脱离受损所致。为了定义调节 DC 从肺部释放的分子相互作用，我们将开发具有重组基质分子的基质，以在体外测试 NLRP10 缺陷的 DC 粘附和迁移；此外，我们将在体内阻断DC附着到肺实质的主要决定因素，以克服NLRP10缺陷小鼠中Th2对空气过敏原的启动失败。如果 NLRP10 的缺失选择性地消除 DC 介导的 CD4+ T 细胞对空气过敏原的启动，那么针对该途径可能使我们能够控制过敏性疾病中致敏和耐受之间的平衡，同时可能保持保护性 CD8+ T 细胞免疫完好无损。因此，完成这些研究后，我们的长期目标是开发一种基于 DC 的方法，通过抑制 NLRP10 途径来治疗过敏性疾病。