Mechanisms of resident memory T cell differentiation controlled by antigen recognition in non-lymphoid tissue

非淋巴组织中抗原识别控制的常驻记忆T细胞分化机制

• 批准号: 10449230
• 负责人: Jeffrey C. Nolz
• 金额: $ 38.21万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449230
• 关键词: Address; Affinity; Antigen-Presenting Cells; Antigens; Autoimmune; Avidity; Bacterial Infections; Biological; Biological Assay; Biological Models; Blood Circulation; CD8-Positive T-Lymphocytes; Cell Compartmentation; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Clinical; Data; Development; Disease; Enterobacteria phage P1 Cre recombinase; Focal Infection; Gene Expression Profile; Generations; Genes; Genetic Transcription; Goals; Hematopoietic; Host Defense; Immunology; Infection; Infectious Skin Diseases; Inflammatory; Interleukin-10; Knowledge; Langerhans cell; Ligands; Listeria monocytogenes; Lymphocytic choriomeningitis virus; Mediating; Memory; Modeling; Molecular; Myelogenous; Peptide/MHC Complex; Peptides; Population; Positioning Attribute; Production; Receptor Signaling; Reporter; Residencies; Shapes; Signal Pathway; Signal Transduction; Skin; Surface; Systemic infection; T cell differentiation; T cell receptor repertoire sequencing; T memory cell; T-Cell Receptor; T-Lymphocyte; Tamoxifen; Testing; Therapeutic; Tissue Differentiation; Tissues; Transgenic Organisms; Vaccine Design; Vaccinia virus; Viral; Virus Diseases; co-infection; cytokine; cytotoxic CD8 T cells; effector T cell; improved; in vivo; innovation; insight; keratinocyte; monocyte; morphogens; pathogen; prevent; skin disorder; treatment strategy

PROJECT SUMMARY/ABSTRACT Tissue-resident memory CD8+ T cells have now been shown to form and persist in nearly every type of non- lymphoid tissue. Because these cells are permanently positioned at environmental barrier surfaces such as the skin, they are believed to be critically important for host defense against pathogens. In fact, tissue-resident memory T cells are more protective than memory T cells in the circulation against a variety of viral and bacterial infections. Infection of the skin with Vaccinia virus (VacV) has emerged as an attractive model system to interrogate the mechanisms that control the formation of highly functional tissue-resident T cell populations. We have recently demonstrated that local recognition of antigen in the tissue microenvironment is critical for the formation of tissue-resident memory CD8+ T cells in non-lymphoid tissues. Specifically, we showed that after effector CD8+ T cells enter the VacV-infected skin, a second antigen encounter causes rapid expression of CD69 and retention of these T cells in the non-lymphoid tissue. In this proposal, we will now define the molecular and transcriptional mechanisms that control the formation of tissue-resident memory CD8+ T cells in the skin microenvironment during a viral infection, as the fundamental immunology that regulates T cell function and memory differentiation in non-lymphoid tissue remains largely undefined. To address this question, we will 1) determine how T cell receptor affinity/avidity for antigen shapes the composition of the tissue-resident memory T cell compartment, 2) determine if a Blimp1/IL-10 signaling axis controls the formation of tissue-resident memory T cells in the skin, and 3) identify the relevant antigen- presenting cells (both hematopoietic and non-hematopoietic) that regulate tissue-residency by presenting peptide and/or other survival factors to CD8+ T cells in the skin during viral infection. The overall goal of this project will be to define the mechanisms that regulate both the formation and function of tissue-resident memory T cell populations, which will contribute to our long-term goal of improving vaccine design and identifying strategies for the treatment of inflammatory disorders of the skin.

项目概要/摘要 组织驻留记忆 CD8+ T 细胞现在已被证明可以在几乎所有类型的非细胞中形成并持续存在。 淋巴组织。因为这些细胞永久位于环境屏障表面，例如 人们认为它们对于宿主防御病原体至关重要。事实上，组织驻留 记忆 T 细胞比循环中的记忆 T 细胞对多种病毒和病毒具有更强的保护作用。 细菌感染。痘苗病毒（VacV）皮肤感染已成为一种有吸引力的模型 系统询问控制高功能组织驻留 T 细胞形成的机制 人口。我们最近证明组织微环境中抗原的局部识别是 对于非淋巴组织中组织驻留记忆 CD8+ T 细胞的形成至关重要。具体来说，我们 结果表明，效应 CD8+ T 细胞进入 VacV 感染的皮肤后，第二次抗原遭遇会导致快速 CD69 的表达以及这些 T 细胞在非淋巴组织中的保留。在本提案中，我们现在将 定义控制组织驻留记忆形成的分子和转录机制 病毒感染期间皮肤微环境中的 CD8+ T 细胞，作为基础免疫学 调节非淋巴组织中的 T 细胞功能和记忆分化在很大程度上仍不清楚。到 为了解决这个问题，我们将 1) 确定 T 细胞受体对抗原的亲和力/亲合力如何塑造 组织驻留记忆 T 细胞区室的组成，2) 确定 Blimp1/IL-10 信号轴是否存在 控制皮肤中组织驻留记忆 T 细胞的形成，并且 3）识别相关抗原 - 呈递细胞（造血细胞和非造血细胞）通过呈递来调节组织驻留 病毒感染期间皮肤中 CD8+ T 细胞的肽和/或其他存活因子。本次活动的总体目标 该项目将定义调节组织驻留蛋白的形成和功能的机制 记忆 T 细胞群，这将有助于我们改善疫苗设计和 确定治疗皮肤炎症性疾病的策略。