Developmental layers of CD8+ T cells in the lymph node

项目摘要/摘要 免疫学中一个长期存在的问题是，为什么一些幼稚的CD8+T细胞成为效应者并在 感染，而另一些则存活下来成为记忆细胞。目前的教条表明，单一的血统 单纯的CD8+T细胞可以产生效应性T细胞或记忆性T细胞，这取决于它们遇到的线索 (炎症、抗原)在感染期间的启动环境中。然而，我们最近发现， 细胞在感染期间采用特定命运的倾向与它们的发育来源有关，即 它们来自胎肝或骨髓中的干细胞群体。我们发现胎儿来源的CD8+ T细胞在成年后最先对感染做出反应，但很快就会成为短暂的效应者。相比之下，成年人- 衍生的CD8+T细胞反应速度较慢，但可产生更多的记忆CD8+T细胞。一个重要的 问题是，为什么在成年动物中，胎儿来源的T细胞是第一个对感染有反应的细胞？回答这个问题 一直是一个挑战，因为我们缺乏关于发育起源如何改变CD8+T细胞的关键信息 在淋巴结内引爆时的位置和行为。为了克服这一挑战，我们成立了一个 与XU实验室合作，对整个淋巴结深度的活T细胞的行为进行成像 在感染期间。我们的假设是，胎儿来源的细胞在成年后也是第一个对感染有反应的细胞。 (A)因为它们在感染前处于淋巴结内的最佳位置，或(B)因为它们对 不同于启动期间淋巴结中的树突状细胞(DC)。为了区分这些可能性， 我们将使用命运图时间戳小鼠和高分辨率三光子(3P)显微镜来绘制 感染过程中淋巴结内CD8+T细胞的发育层数。在完成这些研究后，我们 期望提供一个新的概念框架来解释为什么单个CD8+T细胞在 并以不同的动力学方式募集到淋巴反应中。

Project Summary / Abstract A long-standing question in immunology is why some naïve CD8+ T cells become effectors and die after infection, whereas others survive to become memory cells. The current dogma suggests that a single lineage of naïve CD8+ T cells can give rise to either effector or memory T cells depending on cues they encounter (inflammation, antigen) in the priming environment during infection. However, we recently discovered that the propensity for cells to adopt particular fates during infection is linked to their development origins, i.e., whether they were derived from stem cell populations in the fetal liver or bone marrow. We found that fetal-derived CD8+ T cells are the first to respond to infection in adulthood but rapidly become short-lived effectors. In contrast, adult- derived CD8+ T cells respond with slower kinetics but give rise to more memory CD8+ T cells. An important question is, why are fetal-derived T cells the first to respond to infection in adult animals? Answering this question has been a challenge because we lack critical information on how developmental origin alters CD8+ T cell position and behavior during priming in the lymph node. To overcome this challenge, we have formed a collaboration with the Xu lab to image the behavior of live T cells throughout the entire depth of the lymph node during infection. Our hypothesis is that fetal-derived cells are the first to respond to infection in adulthood either (a) because they are optimally positioned in the lymph node prior to infection, or (b) because they respond differently to dendritic cells (DCs) in the lymph node during priming. To differentiate between these possibilities, we will use fate-mapping ‘timestamp’ mice and high-resolution three-photon (3P) microscopy to map out the developmental layers of CD8+ T cells in the lymph node during infection. Upon completion of these studies, we expect to provide a new conceptual framework to explain why individual CD8+ T cells behave in distinct ways in the lymph node and are recruited into the response with different kinetics.