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.

项目概要： 免疫力下降对老年人的发病率和死亡率有重大影响。 抗原特异性、后天性、尤其是 T 细胞对于宿主防御非常重要 慢性细胞内病原体和癌症。这些微生物和皮肤感染 具有高突变负荷和新表位负荷的癌症，其比例高得不成比例 在老年人中。在此应用中，研究小组使用了已建立的四聚体 和 TCR 工具包，用于研究 T 细胞对水痘带状疱疹病毒感染的反应 （VZV）在人类中确定与年龄相关的带状疱疹易感性机制， 以及一种独特成功的疫苗的作用机制，该疫苗在 老年人。 最近，人们认识到宿主对许多局部感染的防御能力 由特殊的组织驻留记忆细胞群（缩写为 TRM）介导。作为 小鼠和人类研究取得了进展，TRM 谱系、TRM 子集以及 TRM 在各个组织中的转录和代谢特征已经开始出现 成为焦点。 TRM 是局部可移动的，可巡逻组织寻找抗原，并且可以在 抗原再次暴露，但不会重新进入血液，并且超出了基于血液的范围 研究。值得注意的是，对人类抗原特异性 TRM 的研究很少，因此 总体 TRM 人群可能会忽视 TRM 的复杂性。 在这里，我们使用 VZV 感染和疫苗接种作为跨 TRM T 细胞的相关探针 年龄范围。目标 1 侧重于 VZV 的内源性再激活并使用活检 治愈的带状疱疹和控制皮肤，首次全面表征有用的人类 单细胞水平的病毒特异性 TRM。目标 2 使用新型 RZV 疫苗治疗带状疱疹 预防，即使在老年人中也能保持功效，以确定疫苗是否会导致 皮肤中的 TRM 播种，改善皮肤中归巢细胞池 血，或两者兼而有之。总而言之，这些研究将增加我们对年龄的理解 重要效应 T 细胞的相关变化以及可能有助于克服的策略 免疫衰老。