Nedd4-family adaptors and their regulation of T cell function.

Nedd4 家族接头及其对 T 细胞功能的调节。

• 批准号: 8417767
• 负责人: Paula Maria Oliver
• 金额: $ 39.36万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-04 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417767
• 关键词: Accounting; Affinity; Antigens; Asthma; Atopic Dermatitis; Autoantigens; Autoimmune Diseases; CD28 gene; CD3 Antigens; Cell physiology; Cells; Data; Defect; Disease; Failure; Family; Food; Food Hypersensitivity; Gastrointestinal tract structure; Genetic Polymorphism; Goals; Human; IL2RA gene; IgE; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-2; Interleukin-4; Laboratories; Ligands; Lung; Mediating; Mucosal Immunity; Mucous Membrane; Mus; Oral; Ovum; Pathway interactions; Patients; Peptides; Phenotype; Polymorphism Analysis; Production; Proliferating; Proteins; Rag1 Mouse; Receptor Signaling; Regulation; Signal Transduction; Single Nucleotide Polymorphism; Site; Skin; Surface; T-Cell Activation; T-Lymphocyte; Testing; Th2 Cells; Tissues; Work; commensal microbes; cytokine; design; feeding; in vivo; man; prevent; public health relevance; receptor; response; transcription factor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Mucosal surfaces are continuously exposed to harmless foreign antigens such as those from food and commensal bacteria, referred to as environmental antigens. The immune system should be tolerant to these environmental antigens, much as it is to self-antigens. While some mechanisms that regulate tolerance to self and environmental antigens may be shared, others may be unique. We have identified an E3 ubiquitin ligase adaptor, known as Nedd4-family interacting protein 1 (Ndfip1), that regulates T cell tolerance to environmental antigens in mice and man. We recently showed that mice lacking Ndfip1 develop atopic inflammation in lung, skin and GI tract. Additionally, using single nucleotide polymorphism (SNP) analysis, we have identified polymorphisms within the locus that encodes Ndfip1 (located on human Chr5) that are more common in patients with asthma, atopic dermatitis (AD) and inflammatory bowel disease (IBD)2, thus supporting that Ndfip1 regulates atopic disease in both mice and man. Studying Ndfip1-/- mice, we have determined that T cells lacking Ndfip1 become activated and produce Th2 cytokines in response to environmental antigens. We hypothesize that Ndfip1 regulates T cell tolerance by promoting the differentiation of na¿ve T cells into iTregs and by inducing antigen-unresponsiveness. In this proposal, we will 1) determine the mechanism by which Ndfip1 promotes iTreg differentiation by determining whether Ndfip1 is required for iTreg conversion in vitro and in vivo and resolving whether the defect in iTreg conversion of Ndfip1-/- T cells is cell intrinsic or due to their production of IL-4. We will also establish whether Ndfip1 is required for Itch ubiquitylation of TIEG1. We will also 2) test whether Ndfip1-/- T cells require CD28-costimulation to become activated in vivo, use altered peptide ligands in vivo and in vitro to establish whether Ndfip1-/- T cells are activated by lower affinity antigens than WT cells, and determine whether Ndfip1 promotes antigen unresponsiveness in wild type na¿ve T cells by dampening TCR or IL-2R signaling. Finally, we will establish the mechanism(s) underlying these defects. We believe that Ndfip1-dependent pathways could be targeted therapeutically to treat atopic inflammatory diseases such as asthma as well as T cell mediated autoimmune disease. A long-term goal of the laboratory is to design pharmacological mimics of Ndfip1 that would promote its functions therapeutically. The studies we propose will help us toward this goal.

描述(申请人提供)：粘膜表面持续接触无害的外来抗原，如来自食品和共生细菌的抗原，称为环境抗原。免疫系统应该对这些环境抗原有耐受性，就像对自身抗原一样。虽然一些调节自身和环境抗原耐受性的机制可能是共同的，但其他机制可能是独特的。我们已经确定了一个E3泛素连接酶适配器，称为Nedd4家族相互作用蛋白1(Ndfip1)，它调节小鼠和人类T细胞对环境抗原的耐受性。我们最近发现，缺乏Ndfip1的小鼠会在肺、皮肤和胃肠道发生特应性炎症。此外，利用单核苷酸多态(SNP)分析，我们已经确定了编码Ndfip1(位于人类chr5)的基因座内的多态，这种多态在哮喘、特应性皮炎(AD)和炎症性肠病(IBD)2患者中更为常见，从而支持Ndfip1调节小鼠和人类的特应性疾病。在对Ndfip1-/-小鼠的研究中，我们发现缺乏Ndfip1的T细胞会被激活，并产生Th2细胞因子来响应环境抗原。我们假设Ndfip1通过促进NA和T细胞分化为iTregs和通过诱导抗原无反应来调节T细胞耐受性。在本提案中，我们将1)通过确定体外和体内iTreg转化是否需要Ndfip1，以及解决Ndfip1-/-T细胞iTreg转化缺陷是细胞固有的还是由于其产生IL-4来确定Ndfip1促进iTreg分化的机制。我们还将确定TIEG1的Itch泛素化是否需要Ndfip1。我们还将测试Ndfip1-/-T细胞是否需要CD28共刺激才能在体内激活，在体内和体外使用改变的多肽配体来确定Ndfip1-/-T细胞是否被比WT细胞亲和力更低的抗原激活，并确定Ndfip1是否通过抑制TCR或IL-2R信号而促进野生型NAéve T细胞的抗原无应答。最后，我们将建立这些缺陷背后的机制(S)。我们认为，Ndfip1依赖的通路可以作为治疗的靶点，用于治疗特应性炎症性疾病，如哮喘和T细胞介导的自身免疫病。该实验室的长期目标是设计Ndfip1的药理模拟药物，以促进其治疗功能。我们提出的研究将帮助我们实现这一目标。