MECHANISM OF A FUNCTIONAL SWITCH IN GAMMA DELTA T CELLS

最近的观察表明，Gammadelta T细胞可以经历 疾病过程中的功能转换。我们相信 了解这种转换的机制很重要，因为它是 可能是这些细胞在调节细胞周期中所扮演的重要角色 免疫反应。在这项建议中，我们的总体目标是 确定是什么导致Gammadelta T细胞经历功能转换。 我们的具体目标如下： 目的1：检验不同Gammadelta的反应假设 TCR定义的子集与不同的功能相关。使用小鼠 感染了细胞内单核细胞增多性李斯特菌，我们计划 检查VGamma1、VGamma4或VGamma6子集是否显示 感染小鼠细胞因子的差异产生，并评估如何 有选择地移除每个子集会影响疾病的结局。目标2： 为了验证Gammadelta T细胞功能转换的假设 是由Gammadelta T细胞本身控制的。在这里，我们将检查 Gammadelta T细胞是否直接或间接控制其 自身功能切换：1)作为集合功能子集进行响应 当被特定抗原或宿主信号触发时；2)通过刺激 彼此的反应，使得一个Gammadelta T细胞亚群 具有集合函数会引起下一个集合的响应，其集合 功能不同；3)通过诱导某些特定的FasL介导的细胞死亡 Gammadelta T细胞为其他具有不同基因的人的反应让路 功能；4)通过诱导FasL介导的细胞死亡 免疫细胞，从而改变细胞因子环境，可能还会 Gammadelta T细胞的后续功能也是如此。目标3：测试 假设Gammadelta T细胞的功能开关是 受外部因素影响或控制的。我们计划研究一下 正常人外周血中Gammadelta T细胞产生的细胞因子 细胞因子环境已经被扰乱了。我们将重点关注三个不同的 外部感应开关可能发生的方式：1)作为一个整体 转换所有类型的Gammadelta T细胞产生的细胞因子；2) 作为一种基于子集的开关，其中外部细胞因子有利于 一组细胞因子对某些Gammadelta T细胞亚群的刺激作用 超过其他子集的配置文件；以及3)通过渗透的变化 导致相同细胞因子的炎性细胞具有不同的 即使在细胞因子中没有实际的开关， Gammadelta T细胞已经出现。

Recent observations indicate that GammaDelta T cells can undergo a functional switch during the course of disease. We believe that understanding the mechanism of this switch is important because it is probably central to any role these cells play in the regulation of the immune response. In this proposal, our overall objective is to determine what causes GammaDelta T cells to undergo a functional switch. Our specific aims are as follows: Aim 1: to test the hypothesis that responses of different GammaDelta TCR-defined subsets correlate with distinct functions. Using mice infected with the intracellular pathogen Listeria monocytogenes, we plan to examine whether the VGamma1, VGamma4, or VGamma6 subsets show differential cytokine production in infected mice, and to assess how selectively removing each subset affects the disease outcome. Aim 2: to test the hypothesis that functional switching in GammaDelta T cells is controlled by GammaDelta T cells themselves. Here, we will examine whether GammaDelta T cells either directly or indirectly control their own functional switching: 1) by responding as subsets with set functions when triggered by particular antigens or host signals; 2) by stimulating the responses of each other, such that one GammaDelta T cell subset having a set function induces the response of the next, whose set function differs; 3) by inducing FasL-mediated cell death among certain GammaDelta T cells to make way for responses by others having different functions; and 4) by inducing FasL- mediated cell death within other immune cells, thus altering the cytokine milieu and perhaps the subsequent function of GammaDelta T cells as well. Aim 3: to test the hypothesis that the functional switch in GammaDelta T cells is influenced or controlled by external factors. We plan examine the cytokines made by GammaDelta T cells in systems in which the normal cytokine milieu has been perturbed. We will focus on three different ways in which an externally induced switch could occur: 1) as an overall switch in the cytokines produced by GammaDelta T cells of all types; 2) as a subset-based switch in which external cytokines favor the stimulation of certain GammaDelta T cell subsets with a set cytokine profile over other subsets; and 3) via changes in infiltrating inflammatory cells that cause the same cytokines to have different effects, even though no actual switch in cytokines made by the GammaDelta T cells has occurred.