Regulation of T cell homeostasis and memory

了解调节T细胞记忆的机制对于制定保护策略至关重要。 针对流行性和大流行性流感病毒。该项目的目标是确定 粘附分子的选择素家族（E、P和L）和选择素配体PSGL-1与T细胞记忆 最近，我们发现糖基化的，生物活性的选择素配体是由一个子集， 流感病毒感染后引流淋巴结中的CD 4和CD 8效应细胞占大多数 包括IFN-γ或IL-17产生者在内的肺中应答T细胞，Th 1和Th 17的体内相关性 细胞，分别。此外，我们发现记忆表型T细胞表达的一致性分数， 选择素结合活性，表明这是一个稳定的遗传特征，区分记忆的一个子集， 细胞在不存在功能性选择素配体或PSGL-1的情况下，CD 4细胞扩增和定位在CD 4+细胞中。 流感病毒感染后肺部没有改变。然而，CD 4效应子产生升高的IFN-γ水平， 和IL-17提示选择素配体在抑制效应子应答中的作用。重要的是 具有感染后二次扩增能力的记忆性CD 4细胞的发育受损， 可能是因为体内平衡调节的改变。我们的数据支持这样的假设， 由选择素调节的细胞因子对于传递控制CD 4效应细胞应答的信号是必需的， 以及记忆细胞子集的自我平衡维持。我们将研究的新功能（S） 选择素在调节效应T细胞和记忆T细胞中的作用，具体目的如下：1）确定 选择素结合能力的差异鉴定了具有不同功能特性的记忆T细胞亚群， 稳态调节; 2）研究T细胞的选择素依赖性反应和选择素的作用， 流感病毒感染后记忆细胞生成中的结合能力;以及3）鉴定 选择素调节T细胞稳态的机制。我们将利用老鼠， 缺乏PSGL-1-/-的小鼠，缺乏PSGL-1信号传导的小鼠，以及缺乏功能性选择素配体的小鼠， IV/VII岩藻糖基转移酶缺乏。我们将使用IFN-g和IL-17报告小鼠，选择素配体融合 蛋白，WT和工程化流感病毒，使我们能够评估多克隆和 TCR转基因CD 4细胞，并与CDS细胞进行比较。在每一个目标中，我们将合作 与项目1和2一起检查流感模型中定义的CD 4和CD 8细胞亚群。我们将 与项目4合作，该项目将确定选择素在结核病模型中的相关性。 相关性（参见说明）： 这些研究以及项目1、2和4将研究免疫系统 控制肺部感染，并将提供新的见解，调节的发展， 通过调节粘附和迁移的机制来维持记忆T细胞的稳态， 这对帮助保护人口免受急性和慢性感染的战略至关重要。选择素- 结合有可能成为记忆T细胞获得效应子功能的一种新的稳定标志物 这将是一个重要的突破，在临床和基础研究中都非常有价值。

Understanding mechanisms that regulate memory in T cells is crucial for developing strategies to protect against epidemic and pandemic influenza viruses. The goal of this project is to determine the contribution of the selectin family of adhesion molecules (E, P, and L) and the selectin ligand, PSGL-1, to T cell memory Recently, we found that glycosylated, biologically active ligands for selectins are acquired by a subset of CD4 and CD8 effectors in the draining lymph nodes after influenza virus infection and represent the majority of responding T cells in the lungs including IFN-g or IL-17 producers, in vivo correlates of Th1 and Th17 cells, respectively. Moreover, we find that a consistent fraction of memory phenotype T cells express selectin-binding activity, suggesting that this is a stable heritable trait that distinguishes a subset of memory cells. In the absence of functional selectin ligands or PSGL-1, CD4 cell expansion and localization in the lungs after influenza virus infection is unaltered. However, CD4 effectors produce elevated levels of IFN-g and IL-17 suggesting a role for selectin ligands in dampening the effector response. Importantly, the development of memory CD4 cells with the capacity for secondary expansion after infection is impaired, possibly because of altered homeostatic regulation. Our data support the hypothesis that mechanisms regulated by selectins can be essential for the delivery of signals that control CD4 effector cell responses as well as the homeostatic maintenance of a subset of memory cells. We will investigate the novel function(s) of selectins in the regulation of effector and memory T cells in following specific Aims: 1) to determine if differences in selectin-binding capacity identify memory T cell subsets with distinct functional properties and homeostatic regulation; 2) to investigate selectin-dependent responses of T cells and the role of selectin- binding capacity in the generation of memory cells after influenza virus infection; and 3) to identify mechanisms by which selectins regulate T cell homeostasis. We will take advantage of mice that are deficient in PSGL-1-/-, mice that lack PSGL-1 signaling, and mice that lack functional selectin ligands due to deficiency of the IV/VII fucosyl transferases. We will use IFN-g and IL-17 reporter mice, selectin ligand fusion proteins, and WT and engineered influenza viruses to enable us to assess the responses of polyclonal and TCR transgenic CD4 cells and make comparisons to CDS cells. In each of these Aims we will collaborate with Projects 1 and 2 to examine defined subsets of CD4 and CD8 cells in the influenza model. We will collaborate with project 4, which will determine the relevance of selectins in the tuberculosis model. RELEVANCE (See instructions): These studies together with those of projects 1, 2, and 4 will investigate means by which the immune system controls pulmonary infections and will provide new insights into the regulation of the development and homeostasis of memory T cells through mechanisms that regulate adhesion and migration that could be important for strategies to help protect the population from acute as well as chronic infections. Selectin- binding has the potential to be a new stable marker of memory T cells that have achieved effector function This would be an important breakthrough that could be extremely valuable in both clinical and basic studies.