CYTOKINE-MEDIATED T CELL ACTIVATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 短暂的TCR刺激会触发NAVE T细胞进入依赖IL-2的增殖程序，该程序在没有通过TCR进一步激活的情况下继续进行。与天然T细胞不同，记忆T细胞可以通过其TCR或在没有抗原刺激的情况下通过暴露于天然细胞因子如IL-12和IL-18而被激活。这增加了这样一种可能性，即IL-12和IL-18也可能在不需要TCR刺激的情况下，以旁观者激活的形式编程记忆T细胞的增殖。有趣的是，我们发现记忆中的CD8+T细胞在没有同源抗原的情况下会经历细胞因子驱动的“程序性”增殖。此外，我们还发现记忆T细胞的抗原史和细胞因子暴露史直接影响其在LCMV多肽再刺激后细胞因子的表达模式。这些结果表明，记忆性CD8+T细胞的增殖和随后对抗原再刺激的反应性可能受到近期先天(如IL-12、IL-18)或适应性(如TCR)刺激的不同调节。目前的研究主要集中在极大地扩展我们对细胞因子介导的T细胞活化的认识。例如，我们测试了商业上可获得的每一种小鼠细胞因子与其他所有小鼠细胞因子(2000种细胞因子组合)的组合，以确定哪些具有刺激病毒特异性T细胞的能力。我们的结果表明，在暴露后的短短6小时内，有一种新的、以前没有特征的细胞因子组合可以直接激活(或灭活)CD8+T细胞功能。

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. A brief period of TcR stimulation triggers na¿ve T cells into an IL-2-dependent proliferative program that continues in the absence of further activation through the TcR. In contrast to na¿ve T cells, memory T cells can be activated either through their TcR or through exposure to innate cytokines such as IL-12 and IL-18 in the absence of antigenic stimulation. This raised the possibility that IL-12 and IL-18 may also program memory T cell proliferation in a form of 'bystander activation', without the need for TcR stimulation. Interestingly, we found that memory CD8+ T cells undergo cytokine-driven "programmed" proliferation in the absence of cognate antigen. In addition, we found that the antigenic and cytokine-exposure history of memory T cells directly influenced their patterns of cytokine expression following restimulation with LCMV peptide. These results indicate that memory CD8+ T cell proliferation and subsequent responsiveness to antigenic restimulation may be subject to differential regulation by recent innate (e.g., IL-12, IL-18) or adaptive (e.g., TcR) stimulation. Current studies are focused on greatly expanding our knowledge of cytokine-mediated T cell activation. For instance, we have tested every murine cytokine that is commercially available in combination with every other murine cytokine (2,000 cytokine combinations) to determine which ones have the capacity to stimulate virus-specific T cells. Our results indicate that there are new, previously uncharacterized combinations of cytokines that can directly activate (or inactivated) CD8+ T cell functions in as little as 6 hours after exposure.