Understanding the Mechanism of 4-1BB Constimulatiuon

了解 4-1BB 刺激机制

• 批准号: 6614049
• 负责人: Anthony T Vella
• 金额: $ 13.59万
• 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/6614049
• 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(申请人提供)：有几个特征良好的T细胞共刺激信号，没有一个比CD28研究得更多。CD28结合TCR信号诱导T细胞激活，表现为IL-2的分泌和旺盛的增殖。我们对另一种有效的T细胞共刺激分子4-1BB的研究显示了几个有趣的相似之处，但也显示了深刻的差异。在活化的T细胞上结扎4-1BB可诱导类似的功能，如促进细胞因子的分泌和增殖。相反，4-1BB在静息细胞上不表达。然而，也许最显著的不同是在我们的活体模型中，我们已经证明了4-1BB共刺激而不是CD28共刺激可以诱导CD8 T细胞长期存活。生存如何发展的机制尚不清楚，但这是这项提议的一个主要焦点。例如，T细胞是在激活诱导的细胞死亡阶段分裂并大量积累，以至于许多细胞通过稀释而避免死亡，还是因为4-1BB刺激而天生对死亡刺激具有抵抗力？这个问题得到了解决，生存的根本机制是什么的问题也得到了解决。我们将研究哪些细胞群“帮助”4-1BB刺激的T细胞存活，并揭示在抗原刺激和共刺激后生存的要求。作为最初的线索，佐剂和佐剂诱导的细胞因子与4-1BB刺激协同作用可以诱导高水平的长期T细胞存活。重要的是，初步数据显示，许多存活的细胞具有记忆表型。实验旨在确定哪些细胞因子是关键，以及这些细胞因子是如何发挥作用的。也许最令人惊讶的是，4-1BB拯救的CD8 T细胞表现为抑制性细胞，而不是典型的被原型共刺激分子共刺激的典型记忆细胞。结果表明，解救细胞具有阻断CD4T细胞增殖和IL-2产生的能力。这些结果被非常详细地阐述，并最终将支持一个有趣的概念，即并不是所有的共刺激信号的功能都是一致的。