Regulation of memory T cell trafficking by core 2 O-glycan synthesis

通过核心 2 O-聚糖合成调节记忆 T 细胞运输

基本信息

批准号：
10242550
负责人：
Jeffrey C. Nolz
金额：
$ 7.52万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-18 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242550
关键词：
Acute Age Allergens Anabolism Antigens Area Autoantigens Autoimmune Diseases Autoimmunity Basic Science Blood Circulation CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Chronic Complex Disease E-Selectin Endothelium Environment Exhibits Extravasation Gene Expression Profiling Generations Genes Genetic Transcription Glycobiology Goals Home environment Hypersensitivity Immune Immunity Immunotherapy In Vitro Infection Inflammation Inflammatory Integrins Interleukin-15 Life Ligands Link Lymphocyte Homing Receptors Mediating Membrane Proteins Memory Modeling Molecular P-Selectin Pathogenicity Pathologic Pathway interactions Polysaccharides Population Population Heterogeneity Prevention Process Protocols documentation Regulation Research Route Selectins Skin Stat5 protein T memory cell T-Lymphocyte T-Lymphocyte Subsets Techniques Testing Tissues Vaccine Design Vaccines Vascular Endothelium Virus Diseases antiviral immunity base chemokine receptor cytokine experience glycosylation human disease immunopathology improved in vivo innovation lymph nodes memory CD4 T lymphocyte pathogen receptor response trafficking transcription factor vaccine immunotherapy

项目摘要

PROJECT SUMMARY/ABSTRACT Antigen-experienced memory T cells constitute a diverse, heterogeneous population of immune cells that is generated throughout life in response to a variety of pathogens, vaccines, allergens, self-antigens and other environment factors. In fact, as we age, generation of new naïve T cells diminishes and memory T cell populations dominate the repertoire. Thus, the basic mechanisms that regulate the functions of diverse memory T cell populations has broad relevance for a variety of diseases and pathological conditions including vaccine designs, immunotherapy protocols and treatment or prevention of inflammatory or autoimmune disorders. Although the formation and differentiation of memory CD8+ and CD4+ T cells in the circulation has been extensively characterized, the capacity for memory T cells to actively home to and infiltrate tissues where they exhibit their effector functions is less understood. We have recently discovered that memory CD8+ T cells require post-translational O-linked glycosylation of selectin ligands for trafficking to and infiltrating non- lymphoid tissues. Furthermore, we identified that de novo synthesis of core 2 O-glycans is restricted to memory T cells and can be regulated in an antigen-independent manner. However, the basic molecular mechanisms regulating core 2 O-glycan synthesis and trafficking of memory CD8+ and CD4+ T cells during infections are yet to be fully characterized. Specifically, we will 1) determine if different CD8+ T cell populations have the capacity to synthesize core 2 O-glycans and traffic into non-lymphoid tissues, 2) define the molecular and transcriptional mechanisms that regulate core 2 O-glycan synthesis in memory CD8+ T cells, and 3) determine if memory CD4+ T cells require core 2 O-glycan synthesis to traffic into non-lymphoid tissues during either acute or chronic viral infections. Thus, the overall goal of our study will be to identify and characterize the mechanisms regulating the trafficking of diverse memory T cell populations and how this can be enhanced (for host protection) or inhibited (for allergies or autoimmunity).

项目概要/摘要经历过抗原的记忆 T 细胞构成了一个多样化、异质性的免疫细胞群，在整个生命产生过程中，对各种病原体、疫苗、过敏原、自身抗原和其他物质作出反应事实上，随着年龄的增长，新的幼稚 T 细胞和记忆 T 细胞的生成会减少。因此，调节不同功能的基本机制是由种群主导的。记忆 T 细胞群与多种疾病和病理状况具有广泛的相关性，包括疫苗设计、免疫治疗方案以及炎症或自身免疫性疾病的治疗或预防尽管循环中记忆CD8+和CD4+T细胞的形成和分化有障碍。主要特征是记忆 T 细胞主动归巢和渗透组织的能力我们最近发现记忆 CD8+ T 细胞对它们表现出的效应功能知之甚少。需要选择素配体的翻译后O-连接糖基化以运输和渗透非- 此外，我们发现核心 2 O-聚糖的从头合成仅限于淋巴组织。记忆T细胞并且可以以不依赖于抗原的方式进行调节，但是，基本分子。调节核心 2 O-聚糖合成和记忆 CD8+ 和 CD4+ T 细胞运输的机制具体而言，我们将 1) 确定是否存在不同的 CD8+ T 细胞群。具有合成核心 2 O-聚糖并运输到非淋巴组织的能力，2) 定义分子以及调节记忆 CD8+ T 细胞中核心 2 O-聚糖合成的转录机制，以及 3) 确定记忆 CD4+ T 细胞是否需要核心 2 O-聚糖合成来运输到非淋巴组织因此，我们研究的总体目标是识别和表征。调节不同记忆 T 细胞群运输的机制以及如何增强这种机制（用于保护宿主）或抑制（用于过敏或自身免疫）。