CD137 SIGNALS IN DC DURING AG-PRIMING INDUCES TOLERANCE

AG 启动期间 DC 中的 CD137 信号会导致容差

• 批准号: 8172368
• 负责人: ROBERT S MITTLER
• 金额: $ 5.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172368
• 关键词: Adoptive Transfer; Antigen-Presenting Cells; Apoptosis; Biochemical Pathway; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Death; Cell Death Process; Cell Lineage; Cell physiology; Cessation of life; Computer Retrieval of Information on Scientific Projects Database; Dendritic Cells; Event; Funding; Grant; Hematopoietic; Immune response; Institution; Learning; Maintenance; Mediating; Mus; Phosphorylation; Play; Process; Reporting; Research; Research Personnel; Resources; Role; Signal Transduction; Source; T cell anergy; T-Lymphocyte; TNFRSF6 gene; Transgenic Organisms; Tumor Necrosis Factor Ligand Superfamily Member 6; United States National Institutes of Health; Up-Regulation; Virus; anergy; immune self tolerance; receptor; transcription factor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the current reporting period we confirmed that CD137-mediated signaling, an event that leads to protective immune responses by T cells, under appropriate conditions induced suppression of T cell function (anergy). By adoptive transfer of CD137-sufficient SMARTA transgenic CD4 T cells and CD137-sufficient P14 TCR transgenic CD8 T cells into CD137-deficient mice we have learned that CD137-mediated anergy was dependent on CD137 expression on T cells, but while necessary, was insufficient to induce T cell anergy. CD137 signaling in T cells led to up- regulation of the apoptosis-inducing death receptor CD95 (Fas). While examining the function of other hematopoietic cell lineages, we found that CD137-mediated signaling in dendritic cells (DC) was critical to the induction of anergy in virus-specific T cells, and that all major subsets of DCs expressing CD137 could induce T cell anergy. Anergic T cells are ultimately deleted through a process known as activation-induced cell death (AICD) and this process too is DC and CD137-dependent as it induces the upregulation and release of soluble Fas ligand by T cells. From studies geared to understand how CD137 signaling in DCs altered their function such that these antigen-presenting cells led to the induction of anergy and AICD rather than as is normal, the activation of na¿ve T cells, we found that CD137 signaling in DCs led to the rapid activation (phosphorylation) of the transcription factor, Stat3. Others had previously shown that Stat3 signaling in DCs plays a critical role in the maintenance of immune self-tolerance. Current studies are currently underway to indentify the biochemical pathway through which CD137 activates Stat3.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 对于中心来说，它不一定是研究者的机构。 在本报告期内，我们证实 CD137 介导的信号传导（一种导致 T 细胞保护性免疫反应的事件）在适当的条件下通过过继转移足够的 CD137 SMARTA 转基因 CD4 T 细胞诱导 T 细胞功能抑制（无反应性）。和 CD137 充足的 P14 TCR 转基因 CD8 T 细胞注入 CD137 缺陷小鼠中，我们了解到 CD137 介导的无反应性依赖于 T 上的 CD137 表达细胞，但虽然必要，但不足以诱导 T 细胞中的 CD137 信号传导导致凋亡诱导死亡受体 CD95 (Fas) 的上调。 在检查其他造血细胞谱系的功能时，我们发现树突状细胞 (DC) 中 CD137 介导的信号传导对于诱导病毒特异性 T 细胞无反应性至关重要，并且表达 CD137 的所有主要 DC 亚群都可以诱导 T 细胞无反应性 T 细胞最终通过称为激活诱导细胞死亡 (AICD) 的过程被删除，该过程也是 DC 和 CD137 依赖性的，因为它会诱导 T 细胞的上调和释放。 T 细胞可溶性 Fas 配体。 研究旨在了解 DC 中的 CD137 信号传导如何改变其功能，从而使这些抗原呈递细胞导致无反应性和 AICD 的诱导，而不是正常情况下，na 的激活在 T 细胞中，我们发现 DC 中的 CD137 信号传导导致转录因子 Stat3 的快速激活（磷酸化）。目前的研究表明，DC 中的 Stat3 信号传导在维持免疫自我耐受中发挥着关键作用。目前正在鉴定 CD137 激活 Stat3 的生化途径。