The developmental layers in the CD8+ T cell response to chronic infection

项目摘要/摘要 感染后，一小部分效应性CD8+T细胞存活并过渡到长期记忆中 游泳池。鉴于记忆CD8+T细胞是免疫细胞内病原体的关键，我们有必要 了解它们的形成机制。这个问题一直是该领域的前沿问题 几十年。目前的教条表明，单一的幼稚T细胞谱系可以产生不同的短小和 长寿的效应器或记忆T细胞亚群，取决于它们遇到的信号(炎症、抗原) 在感染期间。然而，在上一个资金周期中，我们发现T细胞采用 相反，感染期间的特定命运是在感染之前预先编程的，并在很大程度上由它们的 发育起源。由于我们到目前为止的所有工作都是在急性感染的情况下进行的，主要的 我们更新提案的目标是将我们的研究扩展到慢性感染，在那里我们将确定如何 记忆池中的异质性与反应细胞发育起源的差异有关。 为了实现这一目标，我们将把我们的新型命运地图系统与特性良好的鼠标相结合 LCMV感染模型来剖析内存池中的功能异质性。我们的初步研究 表明与慢性感染相比，成人来源的细胞优先出现功能衰竭 胎儿来源的细胞。然而，成人来源的CD8+T细胞的克隆性耗竭可以通过以下方法防止 胎儿来源免疫细胞的主要调节因子Lin28b的过表达。基于这些发现和我们的 我们假设CD8+T细胞在慢性感染过程中的命运与它们的 发育起源。在第一个目标中，我们将确定发育起源如何改变CD8+T细胞反应 到慢性病原体。在第二个目标中，我们将研究发育起源如何改变基因调控。 慢性感染时CD8+T细胞中的程序。在最后一个目标中，我们将确定如何发展 Lin28b基因的差异影响CD8+T细胞对慢性感染的反应能力。从以下方面获得的知识 这些研究有望更好地了解CD8+T细胞的调节机制 对慢性病原体的反应，这对于制定更精确和有效的恢复战略至关重要 衰竭的CD8+T细胞的功能。

Project Summary/Abstract Following infection, a small percentage of effector CD8+ T cells survive and transition into the long-lived memory pool. Given that memory CD8+ T cells are key to immunity against intracellular pathogens, it is essential that we understand the mechanisms by which they are formed. This question has been at the forefront of the field for decades. The current dogma suggests that a single lineage of naïve T cells can give rise to different short- and long-lived subsets of effector or memory T cells, depending upon the cues (inflammation, antigen) they encounter during infection. However, in the last funding cycle, we discovered that the propensity for T cells to adopt particular fates during infection is, instead, pre-programmed prior to infection, and is largely determined by their developmental origin. As all of our work to date has been performed in the context of acute infections, the major goal of our renewal proposal is to extend our studies to chronic infection, where we will determine how heterogeneity within the memory pool is linked to variation in the developmental origins of the responding cells. To accomplish this goal, we will combine our novel fate mapping system with the well-characterized mouse model of LCMV infection to dissect the functional heterogeneity within the memory pool. Our preliminary studies indicate that adult-derived cells preferentially become functionally exhausted during chronic infection compared to fetal-derived cells. However, clonal exhaustion of adult-derived CD8+ T cells can be prevented by overexpression of Lin28b, a master regulator of fetal-derived immune cells. Based on these findings and our published work, we hypothesize that the fate of CD8+ T cells during chronic infection is linked to their developmental origin. In the first aim, we will determine how developmental origin alters the CD8+ T cell response to chronic pathogens. In the second aim, we will examine how developmental origin alters gene regulatory programs in CD8+ T cells during chronic infection. In the last aim, we will determine how developmental differences in Lin28b influence the ability of CD8+ T cells to respond to chronic infection. Knowledge gained from these studies is expected to provide a better understanding of the mechanisms regulating the CD8+ T cell response to chronic pathogens, which is essential for developing more precise and effective strategies to restore functionality in exhausted CD8+ T cells.