T follicular helper memory cells

滤泡辅助记忆T细胞

• 批准号: 8870007
• 负责人: Jeffrey Scott Hale
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8870007
• 关键词: Acute; Affect; Affinity; Antibodies; Antibody-mediated protection; Antigens; B-Lymphocytes; Bacterial Infections; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Cellular Immunity; Communicable Diseases; Coupled; Cues; DNA Methylation; Development; Effector Cell; Epigenetic Process; Exposure to; Gene Expression; Generations; Genes; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Heterogeneity; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Individual; Infection; Inflammation; Knock-out; Life; Maintenance; Mediating; Memory; Memory B-Lymphocyte; Methylation; Methyltransferase; Mycoses; Parasitic infection; Plasma Cells; Population; Proteins; Reaction; Research Project Grants; Rest; Signal Transduction; Structure of germinal center of lymph node; T cell response; Testing; Vaccination; Vaccines; Viral Antigens; Virus; Virus Diseases; bisulfite sequencing; candidate validation; cytokine; genome wide methylation; improved; in vivo; insight; interest; memory CD4 T lymphocyte; microorganism; novel; pathogen; programs; public health relevance; research study; response; trait; vaccination strategy; whole genome

 DESCRIPTION (provided by applicant): CD4+ T follicular helper cells (Tfh) cells are required to provide help for antigen-specific germinal center B cell responses, thereby promoting the affinity maturation of antibodies and the generation of long-lived plasma cell and memory B cells. Therefore, understanding how Tfh cells develop and exert their effector function is of great interest for efforts to promote antibody-mediated protection against infectious diseases through vaccination. Following acute viral infection, naïve CD4 T cells specific for viral antigen undergo dramatic changes, including robust proliferation, and differentiation to the distinct T helper 1 (Th1) and Tfh cell lineages. Following clearance of virus, subsets of memory Th1 and Tfh cells are maintained, with the ability to recall their lineage-specific functions upon re-exposure to antigen. In Aim1 of this research project, we will investigate how CD4 Tfh effector and memory cells differentiate during viral infection versus immunization with a protein antigen. We will determine whether these different types of immune reactions alter the function and lineage stability of Tfh and Th1 memory cells upon antigenic rechallenge. We will also determine whether repeated boosting with antigen or heterologous infections reinforces Tfh and Th1 lineage commitment, or reprograms these cells to acquire new phenotypic and functional traits. In Aim 2 of this proposal, we will investigate how epigenetic mechanisms mediated by changes in DNA methylation regulate the ability of lineage-committed Tfh and Th1 memory cells to remember their previously programmed effector gene expression, and repress transcription of genes relevant to other T helper lineages. This will be done using genome-wide methylation analysis, validation of candidate loci that are differentially methylated, and functional experiments to determine whether cells re-express unmethylated (poised) and methylated (repressed) loci upon reactivation of memory Tfh and Th1 cells. Finally, we will explore whether new DNA methylation programs are acquired during Tfh and Th1 cell differentiation, and whether this de novo methylation influences the lineage-commitment of memory CD4 T cells. Together, these studies will provide novel understanding into the programming of virus infection- and immunization-induced memory CD4 T cells, which in turn would allow us to direct vaccine- mediated responses toward improved lasting immune protection against infectious diseases.

 描述（由申请人提供）：需要CD4+ T滤泡辅助细胞（Tfh）细胞为抗原特异性生发中心B细胞应答提供帮助，从而促进抗体亲和力成熟以及长寿命浆细胞和记忆B细胞的产生。因此，了解Tfh细胞如何发育并发挥其效应功能是非常重要的 对通过疫苗接种促进抗体介导的针对传染病的保护的努力感兴趣。在急性病毒感染后，对病毒抗原特异性的幼稚CD4 T细胞经历 显著的变化，包括稳健的增殖和分化为不同的T辅助细胞1（Th1）和Tfh细胞谱系。病毒清除后，记忆性Th1和Tfh细胞的亚群得以维持，在再次暴露于抗原时具有回忆其谱系特异性功能的能力。在本研究项目的目标1中，我们将研究CD4 Tfh效应细胞和记忆细胞在病毒感染与蛋白抗原免疫过程中的分化。我们将确定这些不同类型的免疫反应是否会改变抗原再激发后Tfh和Th1记忆细胞的功能和谱系稳定性。我们还将确定抗原或异源感染的重复加强是否会加强Tfh和Th1谱系的承诺，或重新编程这些细胞以获得新的表型和功能性状。在本提案的目标2中，我们将研究DNA甲基化变化介导的表观遗传机制如何调节谱系定型的Tfh和Th1记忆细胞记忆其先前编程的效应基因表达的能力，并抑制与其他T辅助细胞谱系相关的基因的转录。这将使用全基因组甲基化分析，验证差异甲基化的候选基因座，以及功能实验来确定细胞在记忆Tfh和Th1细胞重新激活后是否重新表达未甲基化（平衡）和甲基化（抑制）基因座。最后，我们将探讨在Tfh和Th1细胞分化过程中是否获得了新的DNA甲基化程序，以及这种从头甲基化是否会影响记忆性CD4 T细胞的谱系定型。总之，这些研究将为病毒感染和免疫诱导的记忆性CD4 T细胞的编程提供新的理解，这反过来将使我们能够指导疫苗介导的反应，以改善对感染性疾病的持久免疫保护。