Understanding the Mechanism of 4-1BB Constimulatiuon

了解 4-1BB 刺激机制

• 批准号: 7023905
• 负责人: Anthony T Vella
• 金额: $ 31.86万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7023905
• 关键词: biological signal transduction; cell cell interaction; cell death; cell population study; cytokine; cytotoxic T lymphocyte; genetically modified animals; helper T lymphocyte; interleukin 2; laboratory mouse; leukocyte activation /transformation; surface antigens

DESCRIPTION (provided by applicant): There are several well-characterized T cell costimulatory signals, none of which has been studied more than CD28. CD28 ligation in conjunction with TCR signaling induces potent T cell activation as manifested by the secretion of IL-2 and robust proliferation. Our studies of 4-1 BB, another potent T cell costimulatory molecule, have shown several interesting parallels, but also profound differences. Ligation of 4-1BB on activated T cells induces similar functions, such as heightened cytokine secretion and proliferation. In contrast, however, 4-1BB is not expressed on resting cells. Perhaps the most dramatic difference, however, is in our in vivo models, where we have demonstrated that 4-1BB costimulation, but not CD28 costimulation, induces CD8 T cell long-term survival. The mechanics of how survival develops is unknown, but is a major focus of this proposal. For example, do T cells divide throughout the activation-induced cell death phase and accumulate in massive numbers such that many of them avoid death by dilution, or are they inherently resistant to death stimuli because of 4-1BB stimulation? This issue is addressed, as is the question of what is the underlying mechanism of survival. We will examine which cell populations "help" the 4-1BB stimulated T cells survive and uncover the requirements for survival after Ag stimulation and costimulation. As an initial clue it is clear that adjuvants and adjuvant-inducing cytokines synergize with 4-1BB stimulation to induce high levels of long term T cell survival. Importantly, preliminary data show that many of the surviving cells possess a memory phenotype. Experiments are designed to determine which cytokines are key and how the cytokines function. Perhaps what is most striking is that the 4-1BB-rescued CD8 T cells behave as inhibitory cells rather than typical memory cells which have been costimulated by prototypical costimulatory molecules. It is shown that the rescued cells possess the ability to block CD4 T cell proliferation and IL-2 production. These results are addressed in great detail and ultimately will lend credence to the interesting notion that not all costimulatory signals function in congruence.

描述（由申请人提供）：有几个特征良好的T细胞共刺激信号，没有比CD28多研究。 CD28与TCR信号结合结合，诱导有效的T细胞激活，表现为IL-2的分泌和可靠的增殖。我们对4-1 BB的研究是另一种有效的T细胞共刺激分子，显示了几种有趣的相似之处，但也存在深远的差异。 4-1BB在活化的T细胞上的连接会引起相似的功能，例如细胞因子分泌和增殖的增强。但是，相反，在静息细胞上未表达4-1BB。然而，也许最引人注目的差异是在我们的体内模型中，我们证明了4-1BB共刺激，但没有CD28共刺激，可以诱导CD8 T细胞的长期生存。生存方式发展的机制尚不清楚，但是该提议的主要重点。例如，T细胞会在整个激活诱导的细胞死亡阶段分裂并积聚大量以使其中的许多人避免因稀释而避免死亡，还是由于4-1BB刺激而对死亡刺激具有固有的抵抗？解决了这个问题，以及生存的基本机制是什么。我们将检查哪些细胞群“帮助” 4-1BB刺激的T细胞存活并发现Ag刺激和共刺激后生存的要求。作为初始线索，很明显，辅助和辅助诱导细胞因子与4-1BB刺激协同诱导高水平的长期T细胞存活。重要的是，初步数据表明，许多幸存的细胞都具有记忆表型。实验旨在确定哪些细胞因子是关键以及细胞因子的功能。也许最引人注目的是，4-1BB验证的CD8 T细胞的作用是抑制细胞，而不是典型的记忆细胞，这些记忆细胞已被原型的共刺激分子进行了典型。结果表明，被救出的细胞具有阻断CD4 T细胞增殖和IL-2产生的能力。这些结果详细介绍了这些结果，并最终将对有趣的观念充满信心，即并非所有的共刺激信号都具有一致。