Understanding the Mechanism of 4-1BB Constimulatiuon

描述（由申请人提供）：有几种特征明确的 T 细胞共刺激信号，其中没有一个比 CD28 的研究更多。 CD28 连接与 TCR 信号传导相结合可诱导有效的 T 细胞激活，如 IL-2 的分泌和强劲的增殖所示。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，但也存在深刻的差异。将 4-1BB 连接到活化的 T 细胞上会诱导类似的功能，例如细胞因子分泌和增殖增强。然而，相比之下，4-1BB 在静息细胞上不表达。然而，也许最显着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 CD28 共刺激）可诱导 CD8 T 细胞长期存活。生存发展的机制尚不清楚，但这是该提案的主要焦点。例如，T 细胞是否在激活诱导的细胞死亡阶段进行分裂并大量积累，以便其中许多细胞通过稀释避免死亡，或者它们是否由于 4-1BB 刺激而固有地抵抗死亡刺激？这个问题以及生存的根本机制是什么的问题都得到了解决。我们将检查哪些细胞群“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。作为初步线索，很明显佐剂和佐剂诱导细胞因子与 4-1BB 刺激协同作用，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 CD8 T 细胞表现为抑制细胞，而不是由原型共刺激分子共刺激的典型记忆细胞。结果表明，获救的细胞具有阻断 CD4 T 细胞增殖和 IL-2 产生的能力。这些结果得到了非常详细的阐述，最终将证实一个有趣的概念，即并非所有共刺激信号都一致发挥作用。

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.