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: 10656324
• 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/10656324
• 关键词: Address; Affinity; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Avidity; Bacterial Infections; Biological; Biological Assay; Biological Models; CD8-Positive T-Lymphocytes; Cell Compartmentation; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Circulation; 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; inducible Cre; innovation; insight; keratinocyte; monocyte; morphogens; pathogen; prevent; skin disorder; tissue resident memory T cell; 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.

项目摘要/摘要 组织驻留的CD8+T细胞现在已经被证明在几乎每种类型的非 淋巴组织。因为这些电池永久地位于环境屏障表面，例如 皮肤，他们被认为是至关重要的宿主防御病原体。事实上，组织驻留 与循环中的记忆T细胞相比，记忆T细胞对各种病毒和 细菌感染。皮肤感染痘苗病毒(VacV)已成为一个有吸引力的模式 询问控制高功能组织驻留T细胞形成的机制的系统 人口。我们最近证明了在组织微环境中对抗原的局部识别是 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 显示在效应器CD8+T细胞进入VacV感染的皮肤后，第二次抗原相遇导致迅速 CD69的表达及其在非淋巴组织中的滞留。在这项提案中，我们现在将 确定控制组织驻留记忆形成的分子和转录机制 在病毒感染期间皮肤微环境中的CD8+T细胞，作为 在非淋巴组织中调节T细胞功能和记忆分化在很大程度上仍不清楚。至 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/亲和力如何塑造 组织驻留记忆T细胞室的组合物，2)确定Blimp1/IL-10信号轴 控制皮肤中组织驻留记忆T细胞的形成，以及3)识别相关的抗原- 提呈细胞(包括造血细胞和非造血细胞)，通过提呈来调节组织驻留 在病毒感染期间，皮肤中的CD8+T细胞受到多肽和/或其他生存因子的影响。这个项目的总体目标是 该项目将定义调节组织驻留的形成和功能的机制 记忆T细胞群体，这将有助于我们改进疫苗设计和 确定治疗皮肤炎性疾病的策略。