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：
9757594
负责人：
Jeffrey C. Nolz
金额：
$ 38.23万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9757594
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).

项目摘要/摘要抗原经验的记忆T细胞构成潜水员的免疫细胞中的非均质种群生成一生，以响应各种病原体，疫苗，过敏原，自我抗原和其他环境因素。实际上，随着我们的年龄，新的幼稚T细胞的产生减少和记忆T细胞人口主导着曲目。那，调节潜水员功能的基本机制记忆T细胞群体与各种疾病和病理状况具有广泛的相关性疫苗设计，免疫疗法方案以及治疗或预防炎症或自身免疫性疾病。尽管循环中记忆CD8+和CD4+ T细胞的形成和分化具有被广泛表征，记忆T细胞主动回家和浸润组织的能力他们表现出效应子功能的理解较低。我们最近发现内存CD8+ T细胞需要经过翻译后的O连锁糖基化选择素配体进行运输和渗透非 - 淋巴组织。此外，我们确定核心2 O-Glycans的从头综合仅限于记忆T细胞，可以以抗原无关的方式进行调节。但是，基本分子调节核心2 O-聚糖合成的机制和记忆CD8+和CD4+ T细胞的运输感染尚未充分表征。具体来说，我们将1）确定是否不同的CD8+ T细胞种群有能力将核心2 O-glycans和流量合成为非淋巴组织，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，3）确定记忆CD4+ T细胞是否需要核心2 O-Glycan合成才能在运行到非淋巴组织中急性或慢性病毒感染。这是我们研究的总体目标是识别和表征计算潜水员记忆T细胞种群贩运的机制以及如何增强它（用于宿主保护）或抑制（用于过敏或自身免疫性）。