T cell signal transduction in the regulation of T cell memory in response to infection

项目总结 记忆T细胞在再次遇到病原体时快速有效地做出反应，这要归功于 不同的记忆T细胞集，具有不同的迁移特性和功能。记忆性CD8 T细胞 可大致分为3个亚群：2个高度流动的循环记忆CD8 T细胞亚群，称为中央 效应器记忆T细胞和驻留在非淋巴组织中的记忆T细胞池。其作用机制 来调节内存池中的这种异构性，以及这些子集是相互依赖的，还是 可以操纵特定存储器群的生成以使主机保持未知的优势 田野。我们的初步数据支持后者是可能的，并为 NFkB信号调节T细胞亚群记忆多样性。我们将使用新的可诱导的小鼠模型 调节NFkB信号的强度，机械地定义NFkB信号调节居民和中央的方式 流感感染背景下记忆的产生和维持(目标1)。在目标2中，我们将使用 新的NFkB下游中间体Pim1K的不同损益功能模型 T细胞中的信号，调节T细胞记忆亚群的多样性。我们预计，从 这里提出的研究将具有非常重要的意义。这些研究的数据将推动T细胞存储领域的发展 目前还不清楚每个T细胞记忆亚群是如何调节的。此外，我们预计我们的 结果将提供新的和关键的途径，使我们能够调整驻留记忆的生成 T细胞在屏障组织中为宿主提供优势。这可能与流感感染和 TRM寿命特别有限且对IAV异型免疫至关重要的疫苗接种。

PROJECT SUMMARY Memory T cells rapidly and efficiently respond upon re-encountering pathogens, thanks to the existence of a diverse set of memory T cells with different migratory properties and functional capabilities. Memory CD8+ T cells can be broadly divided into 3 subsets: 2 highly mobile circulating memory CD8+ T cell subsets, termed central and effector memory T cells and a memory T cell pool that is resident in non- lymphoid tissues. The mechanisms that regulate this heterogeneity in the memory pool and whether these subsets are interdependent, or the generation of a specific memory population can be manipulated to the advantage of the host remain unknown in the field. Our preliminary data supports that the latter is possible and provides evidence for a critical role of NFkB signaling regulating T cell subset memory diversity. We will use novel inducible mouse models able to regulate the strength of NFkB signaling to mechanistically define how NFkB signals regulate resident and central memory generation and maintenance in the context of influenza infection (Aim 1). In Aim 2, we will employ different loss and gain of function models to determine how Pim1K, a novel downstream intermediate of NFkB signals in T cells, regulates T cell memory subset diversity. We anticipate that the information resulting from the studies proposed here will be highly significant. Data from these studies will advance the field of T cell memory where it is still unclear how each of the T cell memory subsets is regulated. Additionally, we expect that our results will provide with novel and critical avenues that will permit us to tune the generation of resident memory T cells in barrier tissues for the advantage of the host. This may be especially relevant for influenza infection and vaccination where TRM longevity is specially limited and critical for heterosubtypic immunity to IAV.