Cutaneous pathogen-specific tissue resident memory T cells in human aging

人类衰老过程中皮肤病原体特异性组织常驻记忆 T 细胞

• 批准号: 10228544
• 负责人: David M Koelle
• 金额: $ 56.18万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228544
• 关键词: Adult; Age; Aging; Animals; Antigens; Biological; Biological Assay; Biopsy; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Mobility; Cells; Chronic; Clinical; Contralateral; Cranial Nerves; Cutaneous; Data; Deposition; Elderly; Exanthema; Focal Infection; Ganglia; Gene Expression Profile; Genetic Transcription; Herpes zoster disease; Herpesvirus Type 3; Home; Homing; Host Defense; Human; Immune; Immunity; Immunology; Infection; Intramuscular; Intramuscular Injections; Life; Malignant Neoplasms; Measurement; Measures; Mediating; Memory; Metabolic; Methods; Microbe; Molecular Profiling; Morbidity - disease rate; Mus; Mutation; National Institute of Allergy and Infectious Disease; National Institute of Dental and Craniofacial Research; Natural Immunity; Neurons; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Physiological; Population; Positioning Attribute; Predisposition; Prevention; Primary Infection; Proliferating; Proteins; RNA; Recovery; Rejuvenation; Research; Risk; Risk Factors; Route; Simplexvirus; Site; Skin; Skin Cancer; Special Population; Specificity; Subgroup; T cell response; T memory cell; T-Lymphocyte; Time; Tissues; Twin Multiple Birth; VZV vaccine; Vaccination; Vaccines; Viral; Virus; Virus Diseases; acquired immunity; age effect; age related; aged; base; circulating biomarkers; craniofacial; effector T cell; healing; interest; mRNA Expression; mortality; neoantigens; pathogen; prevent; recurrent infection; senescence; tool; vaccine delivery; vaccine development; vaccine discovery; vaccinology

Project Summary: The waning of immunity has a major impact on morbidity and mortality in the aged. Antigen-specific, acquired, and especially T-cellular is important in host defense against chronic intracellular pathogens and cancer. Infections with these microbes and skin cancers with high mutational burdens and neoepitope loads, are disproportionally high in the elderly. In this application, the investigative team uses an established tetramer and TCR toolkit for the study of T-cell responses to varicella zoster virus infections (VZV) in humans to determine the mechanisms of age-related susceptibility to shingles, and the mechanisms of action of a uniquely successful vaccine that retains efficacy in the elderly. Recently, it has been appreciated that host defense against many localized infections is mediated by special populations of tissue resident memory cells, abbreviated TRM. As murine and human studies have advanced, the lineage of TRM, TRM subsets, and the transcriptional and metabolic signature of TRM in various tissues have begun to come into focus. TRM are locally mobile, patrol tissue for antigen, and can proliferate upon antigen re-exposure, yet do not re-enter the blood and are out of reach of blood-based studies. Notably, studies of human antigen-specific TRM are rare, such that assays of overall TRM populations may overlook the complexity of TRM. Here, we use VZV infection and vaccination as related probes of TRM T-cells across the age spectrum. Aim 1 focuses on endogenous reactivation of VZV and uses biopsies of healed shingles and control skin to, for the first time, fully characterize helpful human virus-specific TRM at the single cell level. Aim 2 uses the new RZV vaccine for shingles prevention, which retains efficacy even in aged adults, to determine if the vaccine leads to TRM seeding in the skin, improvement in the pool of homing-committed cells in the blood, or both. Taken together, these studies will increase our understanding of age- related changes in vital effector T-cells and strategies that may be useful to overcome immune senescence.

项目摘要： 免疫力的减弱对年龄的发病率和死亡率产生了重大影响。 抗原特异性，被收购，尤其是T细胞在宿主防御中很重要 慢性细胞内病原体和癌症。这些微生物和皮肤感染 具有高突变负担和新皮质负荷的癌症，高度高 在老人。在此应用程序中，调查团队使用已建立的四聚体 和TCR工具包，用于研究对水痘带状疱疹病毒感染的T细胞反应 （VZV） 以及保留疗效的独特成功疫苗作用机理 老人。 最近，人们对许多局部感染的托管防御 由缩写的TRM介导的组织驻留记忆细胞介导。作为 鼠类和人类研究已经进步，TRM，TRM子集的谱系以及 各种组织中TRM的转录和代谢特征已开始出现 集中精力。 TRM是本地移动的，用于抗原的巡逻组织，可以在 抗原重新暴露，但不要重新进入血液，并且无法触及血液 研究。值得注意的是，对人类抗原特异性TRM的研究很少见，因此 总体TRM种群可能会忽略TRM的复杂性。 在这里，我们使用VZV感染和疫苗接种作为TRM T细胞的相关探针 年龄频谱。 AIM 1专注于VZV的内源性重新激活并使用活检 愈合的带状疱疹和控制皮肤的人是第一次充分表征有用的人 单细胞水平的病毒特异性TRM。 AIM 2使用新的RZV疫苗作为木瓦 预防，即使在老年人中也保留疗效，以确定疫苗是否导致 为了在皮肤中播种，改善了归巢细胞的池 血液，或两者兼而有之。综上所述，这些研究将增加我们对年龄的理解 可能对克服有用的重要效应子T细胞和策略的相关变化 免疫衰老。