The Basis of Functional Variation in Gamma/Delta T cells

描述(由申请人提供)：当今免疫学中最重要的问题之一涉及如何调节免疫反应。许多细胞类型，包括GammadeltaT细胞，已经被证明影响免疫和炎症反应，但对这一过程是如何进行的知之甚少。小鼠和人类的Gammadelta T细胞的TCR谱相当有限，似乎主要作为具有某些保守的TCR元件的细胞亚群存在，通常以非随机的方式分布。我们最近的研究表明，Gammadelta T细胞亚群在功能上也不同。我们的假设是，感染或炎症诱导特定Gammadelta TCR的配体表达，进而刺激功能不同的Gammadelta细胞亚群的反应，对宿主反应具有不同的影响。这项提议的具体目的是检验这一假设的三个主要影响： 具体目标1-确定Gammadelta TCR的类型和功能在李斯特菌病中是否也是共分离的。我们的假设意味着Gammadelta T细胞亚群在功能上是彼此不同的。我们计划检测和比较三个在李斯特菌感染引起的炎症期间做出反应的Gammadelta T细胞亚群的细胞因子谱，它们在感染期间的增殖能力，以及它们调节巨噬细胞介导的杀死李斯特菌的能力。 特定目标2-检查在李斯特菌感染过程中是否需要TCR刺激才能引起Gammadelta T细胞亚群的反应。我们的假设暗示，Gammadelta T细胞亚群必须被特异性地激活，才能唤起某种功能。如果像我们建议的那样，TCR定义了亚群，那么TCR刺激将是产生两个Gammadelta T细胞亚群反应的关键。我们将使用可溶性TCR多聚体作为竞争性试剂，研究TCR在诱导两个Gammadelta T细胞亚群功能反应中的作用。 具体目标3-确定Gammadelta T细胞亚群影响疾病结局的机制。我们的假设表明，Gammadelta T细胞亚群具有固定的功能。通过过继转移，我们将分别检测三个Gammadelta T细胞亚群对缺乏Gammadelta T细胞的小鼠的李斯特菌感染的影响能力。我们还将研究每个亚群产生特定细胞因子、诱导其他细胞死亡和进行细胞凋亡的能力对疾病结局的重要性。

DESCRIPTION (provided by applicant): One of the most important issues in immunology today involves how immune responses are regulated. A number of cell types, including the (gammadeltaT cells, have been shown to influence immune and inflammatory responses, but little is understood about how this process is carded out. The gammadelta T cells of mice and humans have a quite limited TCR repertoire, and appear to exist largely as subsets of cells having certain conserved TCR elements, often distributed in a nonrandom manner. Our recent studies have indicated that gammadelta T cell subsets also differ functionally from one another. Our hypothesis is that infection or inflammation induces the expression of ligands for particular gammadelta TCRs, which in turn stimulate the responses of functionally distinct gammadelta cell subsets, having diverse effects on the host response. The specific aims of this proposal are to test three major implications of this hypothesis: Specific Aim 1 - to determine whether gammadelta TCR type and function also cosegregate in listeriosis. Our hypothesis implies that gammadelta T cells subsets are functionally distinct from one another. We plan to examine and compare three gammadelta T cell subsets that respond during inflammation induced by Listeria infection for their cytokine profiles, their ability to proliferate during infection, and their ability to modulate macrophage-mediated killing of Listeria. Specific Aim 2 - to examine whether TCR stimulation is required to bring about the response of a gammadelta T cell subset during Listeria infection. Our hypothesis implies that a gammadelta T cell subset must be specifically activated in order to evoke a certain function. If, as we propose, the TCR defines the subset, then TCR stimulation would be critical in bringing about the responses of two gammadelta T cell subsets. We will examine the role of the TCR in eliciting functional responses of two gammadelta T cell subsets using soluble TCR multimers as competetive agents. Specific Aim 3 - to determine the mechanism by which the gammadelta T cell subsets influence disease outcome. Our hypothesis implies that gammadelta T cells subset have fixed functions. Using adoptive transfer, we will examine three gammadelta T cell subsets individually for their ability to influence listerioisis in mice otherwise lacking gammadelta T cells. We will also examine the importance to disease outcome of the ability of each subset to produce particular cytokines, induce the death of other cells, and undergo apoptosis.