Regulation of T cell homeostasis and memory

了解T细胞中调节记忆的机制对于制定保护策略至关重要 预防流行性和大流行性流感病毒。该项目的目标是确定以下项目的贡献 黏附分子选择素家族(E、P和L)及其配体PSGL-1与T细胞记忆的关系 最近，我们发现，糖基化的、具有生物活性的选择素配体是通过以下几个子集获得的 流感病毒感染后引流淋巴结中的CD4和CD8效应物占多数 肺内包括产生干扰素-g或白介素17的反应性T细胞在体内与Th1和Th17的相关性 细胞。此外，我们发现有一致比例的记忆表型T细胞表达 选择素结合活性，表明这是一种稳定的可遗传特征，区分了记忆的一个子集 细胞。在缺乏功能性选择素配体或PSGL-1的情况下，CD4细胞在 流感病毒感染后肺部未发生改变。然而，cd4效应器会产生高水平的干扰素-g。 和IL-17提示选择素配体在抑制效应器反应中的作用。重要的是， 感染后具有二次扩张能力的记忆CD4细胞的发育受到损害， 可能是因为体内平衡调节发生了变化。我们的数据支持这样一种假说 在控制CD4效应细胞反应的信号传递中可能是必不可少的，如 以及存储单元子集的动态平衡维护。我们将考察S在小说中的作用 选择素在调节效应和记忆T细胞中的作用有以下特定目的：1)确定是否 选择素结合能力的差异识别具有不同功能特性的记忆T细胞亚群 2)研究T细胞的选择素依赖的反应及选择素的作用。 流感病毒感染后记忆细胞生成的结合能力；以及3)鉴定 选择素调节T细胞内稳态的机制。我们将利用老鼠的优势 缺乏PSGL-1-/-，缺乏PSGL-1信号的小鼠，以及由于以下原因而缺乏功能性选择素配体的小鼠 IV/VII岩藻糖基转移酶缺乏症。我们将使用干扰素-g和白介素17报告小鼠，选择素配体融合 蛋白质，以及WT和工程流感病毒，使我们能够评估多克隆和 TCR转基因CD4细胞，并与CDS细胞进行比较。在每一个目标上，我们都将通力合作 与项目1和2一起检查流感模型中已定义的CD4和CD8细胞亚群。我们会 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(请参阅说明)： 这些研究与项目1、2和4的研究一起，将调查免疫系统 控制肺部感染，并将提供新的见解，以调节发展和 通过调节黏附和迁移的机制来调节记忆T细胞的动态平衡 这对于帮助保护人民免受急性和慢性感染的战略具有重要意义。选择素- 结合有望成为记忆T细胞实现效应功能的一种新的稳定标记物 这将是一项重要的突破，在临床和基础研究中都具有极其重要的价值。

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.