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Influence of Age on CD4 T Memory Cells

年龄对 CD4 T 记忆细胞的影响

基本信息

批准号：
10633224
负责人：
JORG J GORONZY
金额：
$ 42.29万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10633224
关键词：
ATAC-seq Accounting Adjuvant Adult Age Animal Model Antigens Binding Biogenesis CD4 Positive T Lymphocytes Cell Compartmentation Cell Separation Cell physiology Cells Chromatin Clinical Complement Data Defect Development Early Endosome Educational process of instructing Effector Cell Elderly Endosomes Enzymes Epigenetic Process FOXO1A gene Failure Functional disorder Generations Genes Genetic Transcription Goals Heterogeneity Human Immune Immune system Immunity Immunologic Memory Impairment In Vitro Individual Infection Interferon Activation Interferons Longevity Maps Memory Mitochondria Multivesicular Body Nature Oxidative Phosphorylation Pathway interactions Population Process Recycling Regulation Shapes Signal Transduction System T cell response T memory cell T-Cell Activation T-Lymphocyte Testing Transcriptional Regulation Vaccination Vaccines Viral Virus Virus Diseases WNT Signaling Pathway Zoster Vaccine antigen-specific T cells beta catenin effector T cell epigenetic regulation exhaust experience gene regulatory network glycogen synthase kinase 3 beta human old age (65+)improved in vivo late endosome latent infection memory CD4 T lymphocyte memory process prevent response senescence success synergism tool trait transcription factor transcriptome vaccine response vaccine strategy vaccine trial young adult

项目摘要

PROJECT SUMMARY / ABSTRACT The ability of the immune system to develop immunological memory is the basis for protective immunity induced by infection and vaccination. Generation of memory T cells is governed by transcription factor networks that are different from those regulating effector T cells. Durability of T cell memory is variable, implying that memory T cells are heterogeneous at the level of transcriptional and epigenetic regulation that determine longevity. Protective immunity is increasingly compromised with age, implying a defect in the generation and survival of memory cells. In our in vitro studies of T cell responses from older adults, we found a shift in transcription factor expression that disfavored memory cell generation, in particular a lack of FOXO1 and TCF7 expression. Preliminary evidence suggests that the reduced FOXO1 expression in old activated T cells impairs lysosomal proteolytic activity and induces expansion of the compartment of late endosomes and multivesicular bodies that are able to sequestrate GSK-3β and thereby stabilize β-catenin. In parallel, older activated T cells fail to upregulate the interferon response genes SAMD9 and SAMD9L that bind to early endosomes and facilitate their fusion to mature into late endosome. Inhibition of GSK-3β activity regulates many cellular functions including WNT signaling and TCF7 activity as well as mitochondrial biogenesis, all important processes for memory cell generation and longevity. Based on these data, we propose that older T cells upon activation develop differences in their endosomal/lysosomal system compared to young individuals, with implications for GSK-3β sequestration. We will examine this hypothesis in a mechanistic in vitro Aim 1 and in vivo studies of transcription factor networks in antigen-specific memory T cells in Aim 2. In Aim 1, we will examine how age-associated differences in the expression of the transcription factor FOXO1 and the interferon response genes SAMD9/SAMD9L shape endosomal compartments and how these differences influence signaling and transcription factor pathways that control memory cell development. In Aim 2, we will examine directly ex vivo whether heterogeneity within the memory cell compartment, accounting for differences in protection, correlates with transcription factor networks. We will perform ATAC-seq on antigen-specific memory T cells to infer transcription factor binding and determine the influence of age, nature of inciting virus and vaccine status.

项目摘要/摘要