Novel costimulatory pathways required for T cell regulation

T 细胞调节所需的新共刺激途径

• 批准号: 8495230
• 负责人: Michael Croft
• 金额: $ 43.81万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495230
• 关键词: Accounting; Age; Animals; Antigens; Asthma; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Biology; Bystander Suppression; CD4 Positive T Lymphocytes; Cells; Chronic; Colitis; Data; Dendritic Cells; Development; Disease; Disease model; Failure; Family; Galactose Binding Lectin; Galectin 3; Generations; Genes; Goals; Immune; Immune Tolerance; Immune response; Immunity; Immunosuppressive Agents; Inflammation; Knowledge; Laboratories; Lead; Ligands; Maintenance; Mature T-Lymphocyte; Mediating; Mus; Pathway interactions; Phenotype; Play; Regulation; Regulatory T-Lymphocyte; Reporting; Role; Signal Transduction; Surface; Symptoms; T cell regulation; T cell response; T-Lymphocyte; TNF gene; Testing; Thymus Gland; Tumor Necrosis Factor Receptor; in vivo; member; monocyte; novel; programs; receptor

The control of T cell tolerance versus immunity in part relies on signals from co-stimulatory and co-inhibitory receptors that control various activities of T cells and modulate the suppressive capacity of regulatory T cells (Treg) and regulatory dendritic cells. 4-1 BB (CDI 37, ILA, TNFRSF9), a member of the tumor-necrosis factor receptor (TNFR) super-family, has been characterized as an inducible co-stimulatory molecule on activated T cells. It's recognized ligand, termed 4-1 BBL (TNFSF9), is a member ofthe TNF super-family. Opposed to the positive role that 4-1 BB plays in immunity, we have found a novel inhibitoryrole that does not rely on interaction with 4-1 BBL. The absence of 4-1BB, in gene-deficient animals, leads to an enhanced rather than suppressed responsiveness of T cells to specific antigen, and 4-1BB-deficient mice spontaneously generate autoimmune-type phenotypes with chronic inflammation at the mucosal interfaces, a phenotype not seen in 4-1 BBL-deficient mice. We have found a deficit of Foxp3+ Treg at the mucosal surfaces in mice lacking 4- 1BB, and an inability of mucosal dendritic cells to display normal regulatory activity and induce the development of Foxp3+ Treg. We will test the hypothesis that 4-1 BB modulation ofthe activity of Treg and regulatory dendritic cells accounts for its role in promoting immune tolerance, and pursue the idea that 4-1 BB partnering with new, previously unrecognized, ligands results in regulation of conventional T cell immunity. We have found that 4-1 BB can bind to galecfin-3 and galecfin-9, two reported suppressive molecules, and we will determine whether 4-1BB/galectin interactions account for 4-1 BB negatively regulating T cell responsiveness.

T细胞耐受性与免疫力的控制部分依赖于控制T细胞各种活性的共刺激和共抑制受体的信号，并调节调节性T细胞（Treg）和调节树突状细胞的抑制能力。 4-1 BB（CDI 37，ILA，TNFRSF9）是超家族肿瘤 - 疾病因子受体（TNFR）的成员，已被表征为活化T细胞上诱导的共刺激分子。它被公认的配体称为4-1 bbl（TNFSF9），是TNF超级家族的成员。与4-1 BB在免疫力中发挥的积极作用相反，我们发现了一种新型的抑制性，该抑制性不依赖于4-1 BBL的相互作用。在缺乏基因的动物中，缺乏4-1BB会导致T细胞对特定抗原的反应性增强而不是抑制，而4-1BB缺陷的小鼠自发产生自身免疫性表型，具有慢性炎症在粘膜接口处的慢性炎症，在4-1-1bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-bbl-fickeigent中。我们发现缺乏4-1BB的小鼠的粘膜表面上的Foxp3+ Treg不足，并且粘膜树突状细胞无法表现出正常的调节活性并诱导Foxp3+ Treg的发展。我们将检验以下假设：4-1 BB对Treg和调节树突状细胞的活性调节是其在促进免疫耐受性中的作用，并追求这样一种观念，即4-1 BB与新的，未经认可的配体合作，导致调节常规T细胞免疫。我们发现4-1 Bb可以与两个报道的抑制性分子结合到Galecfin-3和Galecfin-9，我们将确定4-1BB/Galectin的相互作用是否占4-1 Bb的4-1 BB负责调节T细胞响应的情况。