Modeling the ecology of tissue-resident T cells

T细胞是适应性免疫系统的基本组成部分，在暴露于病原体后， 不同的记忆T细胞群持续提供增强的保护以防止再暴露。而 循环记忆T细胞的重要性已经被认识了很多年，只是在过去的几年里， 十年来，已经清楚的是，记忆T细胞的亚群存在于整个外周组织中（已知 作为组织驻留记忆，或T RM），并提供有效的，前线保护免疫。识别 T细胞免疫应答的出现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变 疫苗、疾病和免疫疗法。然而，我们对个体发育、维持和 这些细胞的组织--它们的生态系统--缺乏，甚至在非常基本的水平上。例如，人类保留 T细胞对病原体的免疫力持续数年或数十年，但目前还不清楚这种记忆是否会长期存在 细胞或更动态地，通过自我更新维持和/或由新生成的细胞补充。那里 还有许多其他悬而未决的问题，例如，什么因素支配着T RM的发展和维持 以及我们如何操纵它们来增加它们的数量他们能力的异质性的基础是什么 坚持？T RM是否在克隆内或克隆间相互竞争？他们的空间 在任何竞争动态中的安排发挥作用？T RM龛位内的替换规则是什么？ 在这个建议中，我们将采取多学科的方法来解决这些问题，通过整合数学 以及在小鼠和人类环境中的实验工具。具体而言：（i）我们将使用鼠标 流感感染模型和定量成像，以建立一套经过验证的发展模型， ·通过结合关于时变空间分布的信息， 的T RM在肺，并跟踪预先存在的和新产生的T RM的反应， 在重复感染后，我们将改进这些模型，使其包括竞争和空间生态位，并了解 T-RM之间的相互作用如何影响组织内的替换规则和T-RM的持久性， 细胞记忆体(ii)我们将使用强大的细胞命运绘图系统来模拟细胞的个体发育和稳态 在小鼠一生中在多个组织中天然和组成性产生的TRM，并比较 它们的动力学与显性感染中产生的动力学是一致的。(iii)我们将联合收割机结合独特的人体组织资源 在哥伦比亚与一个新的应用14 C测年的DNA，一个专门的建模框架，和定量 图像分析这种方法将定义抗原驱动的流入和自我更新对细胞增殖的贡献。 T RM稳态，并确定异质性的T RM动力学，跨组织和年龄。 总之，该项目将提供一套定量工具，用于定义组织特异性的生命史。 记忆T细胞，在小鼠和人类中，跨越空间和时间。

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.