Understanding the Mechanism of 4-1BB Constimulatiuon

描述（由申请人提供）：有几种充分表征的T细胞共刺激信号，其中没有一种比CD 28研究得更多。CD 28连接结合TCR信号传导诱导有效的T细胞活化，如通过IL-2的分泌和稳健的增殖所表现的。我们对另一种有效的T细胞共刺激分子4-1 BB的研究显示了一些有趣的相似之处，但也有深刻的差异。活化的T细胞上的4-1BB的连接诱导类似的功能，例如增加的细胞因子分泌和增殖。然而，相反，4-1BB在静息细胞上不表达。然而，也许最显著的差异是在我们的体内模型中，我们已经证明4-1BB共刺激，而不是CD 28共刺激，诱导CD 8 T细胞的长期存活。生存发展的机制尚不清楚，但这是本提案的一个主要焦点。例如，T细胞是否在整个激活诱导的细胞死亡阶段分裂并大量积累，使得它们中的许多通过稀释而避免死亡，或者它们是否由于4-1BB刺激而固有地抵抗死亡刺激？这个问题是解决，因为是什么是生存的根本机制的问题。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Ag刺激和共刺激后存活的要求。作为最初的线索，很明显佐剂和促炎剂诱导细胞因子与4-1BB刺激协同作用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细胞因子如何发挥作用。也许最引人注目的是，4- 1BB拯救的CD 8 T细胞表现为抑制性细胞，而不是典型的记忆细胞，这些记忆细胞已被原型共刺激分子共刺激。结果表明，拯救的细胞具有阻断CD 4 T细胞增殖和IL-2产生的能力。这些结果是非常详细地解决，并最终将提供可信的有趣的概念，即不是所有的共刺激信号功能一致。

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.