Generation, diversity and homeostasis of T cells subsets throughout the body

全身 T 细胞亚群的生成、多样性和稳态

• 批准号: 10426138
• 负责人: Donna L. Farber
• 金额: $ 42.95万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-25 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426138
• 关键词: Activities of Daily Living; Adopted; Age; Allergens; Anatomy; Antigens; Atlases; Autoantigens; Autoimmune; Biological Assay; Biological Models; Blood; Blood Circulation; Bone Marrow; CD8-Positive T-Lymphocytes; CXCR6 gene; Cells; Clone Cells; Disease; Drug or chemical Tissue Distribution; Effector Cell; Epigenetic Process; Exhibits; Generations; Genetic Transcription; Heterogeneity; Homeostasis; Human; Image; Immune; Immune Targeting; Immune response; Immunity; Immunofluorescence Immunologic; Immunologic Memory; Immunotherapy; In Situ; Individual; Infection; Inflammatory; Integrins; Intestines; Laboratories; Life; Lung; Lymphocyte; Lymphoid; Lymphoid Tissue; Maintenance; Mediating; Memory; Mucous Membrane; Mus; Organ Donor; Pathway interactions; Peripheral; Phenotype; Population; Regulation; Research; Signal Transduction; Site; Spleen; T cell differentiation; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Thymus Gland; Time; Tissues; Transcriptional Regulation; Translating; Vaccines; adaptive immunity; base; chemokine receptor; chromatin modification; cytokine; epigenetic profiling; high dimensionality; human tissue; immunopathology; lymph nodes; mouse model; mucosal site; novel; novel marker; pathogen; peripheral blood; programs; response; single-cell RNA sequencing; terminally differentiated effector memory (TEM) T cells; tissue resource; transcriptome; transcriptome sequencing; transcriptomics; tumor

Project 1 Summary T lymphocytes coordinate all aspects of adaptive immunity, including response to pathogens, the maintenance of immunological memory, and also direct many autoimmune and inflammatory diseases. Naive T cells emerge from the thymus, populate the blood and lymphoid tissues where they become activated by new antigens, differentiate into effector cells mediating antigen clearance, with a proportion surviving as long-lived memory T cells. It has been well-established in mouse models that memory T cells are heterogeneous in function and tissue distribution, while in humans T cells have largely been studied from peripheral blood. Recently, my laboratory and others identified a subset of tissue resident memory T cells (TRM) in mouse mucosal and barrier sites that are generated following infection, specifically retained in tissue sites of infection and mediate optimal protective responses to site-specific infections. TRM can also be generated to vaccines, tumors, allergens and autoantigens, indicating the potential importance of this key subset in immune protection and immunopathology. In the previous period of support, we have made novel use of a unique human tissue resource established as part of this Program to reveal how the major T cell subsets are distributed throughout the body at all stages of human life, generating an atlas of human T cell responses in space and time. Notably, we identified memory T cells as the predominant population in blood and multiple tissue sites, with TRM- phenotype cells comprising the majority of memory T cells in all tissues, including lymph nodes, spleen, bone marrow and mucosal sites. By whole transcriptome profiling by RNAseq, we identified a core signature for TRM in lymphoid and mucosal sites distinct from circulating TEM cells including expression of specific integrins, chemokine receptors, inhibitory molecules, and cytokines. These findings suggest a common precursor for TEM and TRM cells, likely derived from the initial activated and differentiated T cells. Our central hypothesis is that TRM and TEM derive from common precursors, but that TRM adopt tissue-specific differentiation and epigenetic profiles due to their localization and maintenance in specific sites. In the proposed research, we will dissect pathways for the generation and maintenance of tissue-resident memory T cells (TRM) relative to circulating effector-memory T cells (TEM) and assess whether TRM heterogeneity is based on function and/or localization. The proposed studies will elucidate mechanisms by which human TRM become localized in specific sites, and the effects of tissue niche in their signaling and function of great importance for optimizing tissue targeting of immune responses in vaccines and immunotherapies.

项目1摘要 T淋巴细胞协调获得性免疫的各个方面，包括对病原体的反应，维持 免疫记忆，并指导许多自身免疫性和炎症性疾病。初生T细胞涌现 从胸腺进入血液和淋巴组织，在那里它们被新的抗原激活， 分化为介导抗原清除的效应细胞，其中一部分存活为长寿记忆T细胞 细胞。在小鼠模型中，记忆T细胞在功能上是不同的，并且 组织分布，而在人类中，T细胞在很大程度上是从外周血中研究的。最近，我的 实验室和其他人在小鼠粘膜和其他组织中发现了组织驻留记忆T细胞(TRM)的一个亚群 感染后产生的屏障部位，特别是保留在感染组织部位并介导 对特定部位感染的最佳保护性反应。TRM也可以用于疫苗、肿瘤、 过敏原和自身抗原，表明这一关键亚群在免疫保护和 免疫病理学。在之前的支持期间，我们新颖地使用了一种独特的人体组织 作为该计划的一部分建立的资源，以揭示主要T细胞亚群是如何分布在整个 人体在人类生命的所有阶段，生成了人类T细胞在空间和时间上的反应图谱。值得注意的是， 我们确定记忆T细胞是血液和多个组织部位的主要群体，通过TRM- 表型细胞包括所有组织中的大多数记忆T细胞，包括淋巴结、脾、骨 骨髓和粘膜部位。通过RNAseq对整个转录组的分析，我们确定了一个核心签名 淋巴和粘膜部位的TRM不同于循环的TEM细胞，包括特异性的表达 整合素、趋化因子受体、抑制分子和细胞因子。这些发现表明了一个共同的 Tm细胞和TRM细胞的前体，可能来源于最初激活和分化的T细胞。我们的中央 假设TRM和TEM来源于共同的前体，但TRM采用组织特异性 由于它们在特定位置的定位和维护而产生的分化和表观遗传学特征。在 在提出的研究中，我们将剖析组织驻留记忆T的产生和维持的途径 细胞(TRM)与循环效应记忆T细胞(TEM)的关系，并评估TRM的异质性是否 基于功能和/或本地化。拟议中的研究将阐明人类TRM的机制 变得局限于特定的位置，以及组织生态位在其信号和功能中的作用 在疫苗和免疫疗法中优化免疫反应的组织靶向性的重要性。