Modeling the ecology of tissue-resident T cells

组织驻留 T 细胞的生态学建模

• 批准号: 10632031
• 负责人: Donna L. Farber
• 金额: $ 100.59万
• 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/10632031
• 关键词: Acute; Adaptive Immune System; Address; Age; Antigens; Atmosphere; Birth; Carbon; Cell Maintenance; Cell Survival; Cells; Collaborations; DNA; Dedications; Development; Disease; Ecology; Epithelium; 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 Dynamics; Population Heterogeneity; Process; Proliferating; Role; Site; Spatial Distribution; Spleen; Structure; System; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Time; Tissue Model; Tissues; Vaccines; Virus Diseases; age related; 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 mapping; tissue resident memory T cell; 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细胞是适应性免疫系统的基本组成部分，在接触病原体后， 不同群体的记忆T细胞持续存在，以提供增强的保护，防止再次暴露。而当 多年来，人们一直意识到循环记忆T细胞的重要性，但这只是在过去的几年里 十年来，记忆T细胞的亚群显然存在于周围组织中(已知 作为组织驻留记忆，或T RM)，并提供强大的一线保护性免疫力。身份识别 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 在疫苗、疾病和免疫疗法方面。然而，我们对个体发育、维护和 这些细胞的组织--它们的生态--缺乏，甚至在非常基本的水平上也是如此。例如，人类保留了 T细胞对病原体的免疫力可持续数年或数十年，但目前尚不清楚这种记忆是否会持续那么长时间 细胞或更动态地，通过自我更新和/或由新生成的细胞补充来维持。那里 是否还有许多其他悬而未决的问题；例如，哪些因素支配着TRM的开发和维护 我们如何才能操纵他们来增加他们的人数？他们能力异质性的基础是什么？ 坚持下去吗？T-RM是在克隆内还是克隆间相互竞争？他们的空间角色是什么？ 安排在竞争中起到了什么作用？在T RM利基市场中的替代规则是什么？ 在这项提案中，我们将采取多学科的方法来解决这些问题，通过整合数学 以及在鼠标和人类环境中的实验工具。具体来说：(I)我们将使用鼠标 流感感染模型及定量成像构建一套有效的发育模型 通过结合关于时变空间分布的信息来研究Trm·的动态平衡 并跟踪预先存在的和新产生的T细胞在肺中的反应。 在反复感染之后，我们将改进这些模型，以包括竞争和空间利基，并理解 T细胞之间的相互作用如何影响组织内的替换规则和T细胞的持久性 细胞记忆。(Ii)我们将使用一个强大的细胞命运映射系统来模拟 在小鼠的整个生命周期中，在多个组织中自然地和结构性地产生的TRM，并比较 它们的动态与在公开感染中产生的那些相比。(三)我们将结合独特的人体组织资源 在哥伦比亚大学，使用了DNA 14C测年的新应用，一个专门的建模框架，以及定量 图像分析。这种方法将定义抗原驱动的涌入和自我更新对 T rM动态平衡，并确定跨组织和年龄的T rm动态的异质性。 总而言之，这个项目将提供一套量化工具来定义特定组织的生活史 记忆T细胞，在老鼠和人类中，跨越空间和时间。

项目成果

Towards a unified model of naive T cell dynamics across the lifespan.

• DOI: 10.7554/elife.78168
• 发表时间: 2022-06-09
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Rane, Sanket;Hogan, Thea;Lee, Edward;Seddon, Benedict;Yates, Andrew J.
• 通讯作者: Yates, Andrew J.

Global estimates of the fitness advantage of SARS-CoV-2 variant Omicron.

• DOI: 10.1093/ve/veac089
• 发表时间: 2022
• 期刊: Virus evolution
• 影响因子: 5.3

Quantifying cellular dynamics in mice using a novel fluorescent division reporter system.

• DOI: 10.3389/fimmu.2023.1157705
• 发表时间: 2023
• 期刊: Frontiers in immunology
• 影响因子: 7.3

Estimation of introduction and transmission rates of SARS-CoV-2 in a prospective household study.

前瞻性家庭研究中 SARS-CoV-2 引入和传播率的估计。

• DOI: 10.1101/2023.06.02.23290879
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: vanBoven,Michiel;vanDorp,ChristiaanH;Westerhof,Ilse;Jaddoe,Vincent;Heuvelman,Valerie;Duijts,Liesbeth;Fourie,Elandri;Sluiter-Post,Judith;vanHouten,MarliesA;Badoux,Paul;Euser,Sjoerd;Herpers,Bjorn;Eggink,Dirk;deHoog,Marieke