Modeling the ecology of tissue-resident T cells

组织驻留 T 细胞的生态学建模

• 批准号: 10241910
• 负责人: Donna L. Farber
• 金额: $ 99.99万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-19 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10241910
• 关键词: Acute; Adaptive Immune System; Address; Age; Antigens; Birth; Carbon; Cells; Collaborations; DNA; Development; Disease; Ecology; Epithelial; Exposure to; Generations; Growth; Heterogeneity; Homeostasis; Human; Image; Image Analysis; Imaging Device; Immunity; Immunologist; Immunotherapy; Infection; Life; Longevity; Lung; Lymphocyte; Maintenance; Maps; Mass Spectrum Analysis; Mathematics; Measures; Memory; Modeling; Monitor; Mucous Membrane; Mus; Nuclear; Organ Donor; Peripheral; Play; Population; Population Heterogeneity; Process; Role; Site; Spatial Distribution; Spleen; Structure; System; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Time; Tissues; Vaccines; Virus Diseases; age related; base; cell age; defined contribution; diverse data; draining lymph node; experience; fitness; human old age (65+); human tissue; influenza infection; interdisciplinary approach; life history; mouse model; novel; pathogen; pathogen exposure; quantitative imaging; recruit; residence; response; self-renewal; spatiotemporal; tissue resource; tool

T cells are fundamental components of the adaptive immune system, and following exposure to a pathogen, diverse populations of memory T cells persist to provide enhanced protection against re-exposure. While the importance of circulating memory T cells has been appreciated for many years, it is only over the last decade that it has become clear that subsets of memory T cells reside throughout peripheral tissues (known as tissue-resident memory, or T RM) and provide potent, front-line protective immunity. The identification of T RM has resulted in a paradigm shift in the way we need to monitor, target and promote T cell immunity in vaccines, diseases and immunotherapies. However, our understanding of the ontogeny, maintenance, and organization of these cells - their ecology - is lacking, even at a very basic level. For instance, humans retain T-cell immunity to pathogens for years or decades, but it is unclear whether this memory persists as long-lived cells or more dynamically, sustained by self-renewal and/or supplemented by newly generated cells. There are many other open questions; for example, what factors govern the development and maintenance of T RM and how might we manipulate them to boost their numbers? What underlies heterogeneity in their capacity to persist? Do T RM compete with each other, either intra- or inter-clonally? What role does their spatial arrangement play in any competitive dynamics? What are the rules of replacement within T RM niches? In this proposal we will take a multidisciplinary approach to addressing these questions by integrating mathematical and experimental tools in both mouse and human settings. Specifically: (i) We will use a mouse model of influenza infection and quantitative imaging to build a set of validated models of the developmental and homeostatic dynamics of T RM· By combining information regarding the time-varying spatial distribution of T RM in the lung, and tracking the responses of pre-existing and newly generated T RM during and after repeat infections, we will refine these models to include competition and spatial niches, and to understand how interaction between T RM influences the rules of replacement within tissues and the durability of T cell memory. (ii) We will use a powerful cell fate-mapping system to model the ontogeny and homeostasis of T RM that are naturally and constitutively produced in multiple tissues across the mouse lifetime, and compare their dynamics to those produced in overt infections. (iii) We will combine a unique human tissue resource at Columbia with a novel application of 14C dating of DNA, a dedicated modeling framework, and quantitative image analysis. This approach will define the contributions of antigen-driven influx and self-renewal to T RM homeostasis, and identify heterogeneity in T RM dynamics, across tissues and ages. In summary, this project will deliver a suite of quantitative tools for defining the life-histories of tissue-specific memory T cells, in both mice and humans, across space and time.

T细胞是自适应免疫系统的基本成分，在暴露于病原体之后， 多种记忆T细胞的种群持续存在，可增强防止重新暴露的保护。尽管 多年来，循环记忆T细胞的重要性已受到赞赏，仅在最后一次 十年已经清楚地表明，记忆T细胞的亚集存在于整个周围组织（已知 作为居住的记忆，或T rm），并提供潜在的一线保护免疫权。标识 T rm导致了我们需要监测，靶向和促进T细胞免疫的方式的范式转移 在疫苗，疾病和免疫疗法中。但是，我们对个体发育，维护和 这些细胞的组织 - 它们的生态 - 甚至在非常基本的水平上也缺乏。例如，人类保留 T细胞对病原体的免疫数年或几十年 细胞或更动态的，由自我更新和/或由新产生的细胞补充。那里 还有许多其他开放问题；例如，哪些因素控制着T RM的发展和维护 我们如何操纵它们以增加他们的数字？什么是其能力异质性的基础 坚持吗？ T rm是否会在环内或环上相互竞争？他们的空间角色是什么角色 安排在任何竞争动态中发挥作用？在TRM壁nife中，更换的规则是什么？ 在此提案中，我们将采用多学科的方法来通过整合数学来解决这些问题 以及鼠标和人类设置中的实验工具。具体：（i）我们将使用鼠标 影响力感染和定量成像的模型，以建立一组经过验证的发展模型 通过结合有关时变空间分布的信息和T rm的稳态动力 肺中的T rm，并跟踪在和新生成的trm和新生成的响应 重复感染后，我们将完善这些模型以包括竞争和空间壁ni，并了解 T rm之间的相互作用如何影响组织内的替代规则和T的耐用性 手机内存。 （ii）我们将使用强大的细胞命运映射系统来建模 自然和组成型在整个鼠标寿命的多个时间上产生的t rm，并比较 它们对明显感染产生的动力。 （iii）我们将结合独特的人体组织资源 在哥伦比亚，具有14C年代DNA的新颖应用，一个专用的建模框架和定量 图像分析。这种方法将定义抗原驱动的影响和自我更新对 T RM稳态，并识别跨组织和年龄的T RM动力学中的异质性。 总而言之，该项目将提供一套定量工具，用于定义组织特异性的生活新闻 在小鼠和人类中，记忆T细胞遍布空间和时间。