Developmental layers of CD8+ T cells in the lymph node

淋巴结中 CD8 T 细胞的发育层

基本信息

批准号：
10648406
负责人：
Brian David Rudd
金额：
$ 23.5万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-03 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10648406
关键词：
Adopted Adult Antigen-Presenting Cells Antigens Behavior Bone Marrow CD8-Positive T-Lymphocytes CXCR3 gene Cell Communication Cell Compartmentation Cells Collaborations Cues Data Dendritic Cells Development Disparate Environment Exhibits Fetal Liver Frequencies Grant Hematopoietic stem cells Image Image-Guided Surgery Imaging Device Immune Immune response Immune system Immunological Models Immunology Individual Infection Inflammation Kinetics Life Link Location Macrophage Maps Measures Memory Metabolic Microscopy Mus Photons Positioning Attribute Primary Infection Resolution Role Secondary to Surveys System T cell response T memory cell T-Cell Activation T-Lymphocyte Testing Time Vaccinia virus Work cell behavior fetal fetus cell intravital imaging lymph nodes lymphoid organ mature animal novel pathogen real-time images recruit response secondary infection stem cell population success tool

项目摘要

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.

项目概要/摘要免疫学中一个长期存在的问题是，为什么一些初始 CD8+ T 细胞成为效应细胞并在死亡后死亡？感染，而其他细胞则存活下来并成为记忆细胞。目前的教条表明，只有一个谱系。初始 CD8+ T 细胞可以根据它们遇到的线索产生效应 T 细胞或记忆 T 细胞（炎症、抗原）在感染过程中的启动环境中然而，我们最近发现。细胞在感染过程中采取特定命运的倾向与其发育起源有关，即，是否它们源自胎儿肝脏或骨髓中的干细胞群，我们发现胎儿来源的 CD8+。 T 细胞在成年后首先对感染做出反应，但很快就会成为短暂的效应细胞。衍生的 CD8+ T 细胞反应动力学较慢，但会产生更多的记忆 CD8+ T 细胞，这一点很重要。问题是，为什么胎儿来源的 T 细胞最先对成年动物的感染做出反应？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 细胞的关键信息为了克服这一挑战，我们形成了一个在淋巴结启动过程中的位置和行为。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我们的假设是，胎儿来源的细胞在成年后最先对感染做出反应。 (a) 因为它们在感染前位于淋巴结中的最佳位置，或 (b) 因为它们有反应与启动过程中淋巴结中的树突状细胞 (DC) 不同，为了区分这些可能性，我们将使用命运图谱“时间戳”小鼠和高分辨率三光子（3P）显微镜来绘制感染期间淋巴结中 CD8+ T 细胞的发育层。期望提供一个新的概念框架来解释为什么个体 CD8+ T 细胞在淋巴结并被招募到具有不同动力学的反应中。