Novel PTPRD interaction Controlling T cell Responsiveness

新型 PTPRD 相互作用控制 T 细胞反应

• 批准号: 9077779
• 负责人: Michael Croft
• 金额: $ 26.55万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9077779
• 关键词: Age; Agonist; Animals; Antibodies; Antigens; Autoantigens; Autoimmune Process; Autoimmunity; B-Lymphocytes; Binding; Binding Proteins; Binding Sites; CD28 gene; Cells; Characteristics; Chimeric Proteins; Clonal Expansion; Cysteine-Rich Domain; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Dendritic Cells; Disease; Equilibrium; Evaluation; Family; Fibronectins; Generations; Genes; Goals; Government; Grant; Hypersensitivity; Immune System Diseases; Immune system; Immunity; Immunology; In Vitro; Inflammation; Inflammatory; Institutes; Knowledge; Lead; Ligands; Ligation; Light; Malignant Neoplasms; Mediating; Membrane; Mus; Nature; PTPRC gene; Pathogenesis; Persons; Phenotype; Physiological; Production; Protein Isoforms; Protein Tyrosine Phosphatase; Rest; Role; Signal Transduction; Surface; Symptoms; T cell response; T-Lymphocyte; TNF gene; Testing; Tumor Antigens; Tumor Necrosis Factor Receptor; Viral; Viral Antigens; Virus; base; delta opioid receptor; high risk; high voltage electron microscopy; in vivo; inhibitor/antagonist; member; novel; public health relevance; receptor; response; tumor; tumor growth; tumor necrosis factor receptor superfamily member 4

 DESCRIPTION (provided by applicant): T cell responsiveness relies on the balance of signals from co-stimulatory and co-inhibitory interactions that control various activities directly in T cels or indirectly in APC. Interestingly, there are a number of molecules that have both stimulatory and inhibitory activity as they can interact with more than one partner, typified by CD86 binding both CD28 and CTLA-4, and HVEM binding LIGHT and BTLA. These interactions then have potential relevance in multiple immune diseases including autoimmunity and cancer. 4-1BB (CD137, TNFRSF9), a member of the tumor-necrosis factor receptor (TNFR) super-family, was originally identified as an inducible co-stimulatory molecule on activated T cells that promotes clonal expansion and survival in effector T cells when it interacts with its recognized TNF family ligand (4-1BBL, TNFSF9). In contrast we have found an early inhibitory role for 4-1BB that does not rely on interaction with 4-1BBL, such that the absence of 4-1BB on naïve T cells leads to enhanced expansion and differentiation. Furthermore, 4-1BB-deficient mice spontaneously develop an autoimmune-type phenotype with inflammation at the mucosal interfaces. We have now found that 4-1BB can bind to protein tyrosine phosphatase (PTP) receptor delta (PTPRD), a putative inhibitory molecule that is expressed on B cells and dendritic cells. Since the identification of CD45 as a membrane-expressed receptor that has PTP activity, a number of other membrane-bound PTP receptors have been described. However, their significance to T cell immunity has not been appreciated. We hypothesize that ligation of PTPRD suppresses maturation and activation of APC and limits the ability of APC to promote strong T cell priming. The studies in this grant will investigate the nature of the interaction of 4-1BB with PTPRD and determine with PTPRD-deficient mice and APC how PTPRD contributes to regulating the generation of T cell immunity. We hypothesize that PTPRD will be a new example of a checkpoint inhibitor of relevance to autoimmunity and cancer.

 描述(申请人提供)：T细胞的反应性依赖于来自共刺激和共抑制相互作用的信号的平衡，这些相互作用直接控制T细胞中的各种活动或间接控制APC中的各种活动。有趣的是，有一些分子既有刺激活性又有抑制活性，因为它们可以与不止一个伴侣相互作用，典型的是CD86结合CD28和CTLA-4，以及HVEM结合LIGH和BTLA。这些相互作用在包括自身免疫和癌症在内的多种免疫疾病中具有潜在的相关性。4-1BB(CD137，TNFRSF9)是肿瘤坏死因子受体(TNFR)超家族的成员之一，最初被发现是活化T细胞上的一种可诱导的共刺激分子，当它与其公认的肿瘤坏死因子家族配体(4-1BBL，TNFSF9)相互作用时，可促进效应性T细胞的克隆性增殖和存活。相反，我们发现了4-1BB的早期抑制作用，这种作用不依赖于与4-1BBL的相互作用，从而使幼稚T细胞上4-1BB的缺失导致增殖和分化的增强。此外，4-1BB基因缺陷的小鼠自发形成一种自身免疫型表型，在粘膜界面有炎症。我们现在发现4-1BB可以与蛋白酪氨酸磷酸酶(PTP)受体Delta(PTPRD)结合，PTPRD是一种可能的抑制分子，表达在B细胞和树突状细胞上。自从CD45被确定为具有PTP活性的膜表达受体以来，许多其他膜结合的PTP受体已经被描述。然而，它们对T细胞免疫的意义还没有被认识到。我们推测，PTPRD的结扎抑制了APC的成熟和激活，并限制了APC促进强大T细胞启动的能力。这项研究将调查4-1BB与PTPRD相互作用的性质，并通过PTPRD缺陷小鼠和APC确定PTPRD如何有助于调节T细胞免疫的产生。我们假设PTPRD将成为与自身免疫和癌症相关的检查点抑制物的新例子。