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免疫应答如何调节。许多细胞类型，包括γ δ T细胞，已被证明会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γ δ T细胞具有相当有限的TCR库，并且似乎主要作为具有某些保守TCR元件的细胞亚群存在，通常以非随机方式分布。我们最近的研究表明，γ δ T细胞亚群在功能上也彼此不同。我们的假设是，感染或炎症诱导特定γ δ TCR的配体表达，这反过来刺激功能不同的γ δ细胞亚群的反应，对宿主反应具有不同的影响。本提案的具体目的是检验这一假设的三个主要含义： 具体目标1 -确定γ δ TCR类型和功能是否也在阿尔茨海默病中共分离。我们的假设意味着γ δ T细胞亚群在功能上彼此不同。我们计划检查和比较三种γ δ T细胞亚群，它们在李斯特菌感染诱导的炎症过程中响应的细胞因子谱，它们在感染过程中增殖的能力，以及它们调节巨噬细胞介导的李斯特菌杀伤的能力。 具体目标2 -检查在李斯特菌感染期间是否需要TCR刺激来引起γ δ T细胞亚群的应答。我们的假设意味着γ δ T细胞亚群必须被特异性激活，以唤起某种功能。如果像我们提出的那样，TCR定义了亚群，那么TCR刺激在引起两个γ δ T细胞亚群的反应中将是至关重要的。我们将研究的作用，在引发功能性反应的两个γ δ T细胞亚群使用可溶性TCR多聚体作为竞争剂的TCR。 具体目标3 -确定γ δ T细胞亚群影响疾病结局的机制。我们的假设意味着γ δ T细胞亚群具有固定的功能。使用过继转移，我们将分别检查三个γ δ T细胞亚群对缺乏γ δ T细胞的小鼠的免疫功能的影响。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.