Modulating costimulation pathways to improve follicular helper T cell and antibody responses

调节共刺激途径以改善滤泡辅助 T 细胞和抗体反应

• 批准号: 10571687
• 负责人: Hai-Hui Xue
• 金额: --
• 依托单位: VA NEW JERSEY HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571687
• 关键词: ATAC-seq; Acute; Address; Antibody Affinity; Antibody Formation; Antibody Response; Attention; Attenuated; B-Lymphocytes; BACH2 gene; Belief; CD28 gene; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Maturation; Cell physiology; Chromatin; Communicable Diseases; Data; Funding; Gene Expression Regulation; Generations; Genetic; Genetic Complementation Test; Genetic Transcription; Genome; Genomics; Helper-Inducer T-Lymphocyte; Immunity; Immunization; Immunologic Memory; Infection; Knowledge; LoxP-flanked allele; Maps; Memory; Memory B-Lymphocyte; Military Personnel; Molecular; Mutant Strains Mice; Mutation; NF-kappa B; Nuclear; Organism; Output; PDPK1 gene; PIK3CG gene; Pathway interactions; Phase; Plasma Cells; Proteins; Role; Route; SOX4 gene; Services; Signal Transduction; Specific qualifier value; Stimulus; Structure of germinal center of lymph node; Testing; Vaccination; Vaccine Design; Vaccines; Veterans; Viral Proteins; Virus; Virus Diseases; acute infection; design; disease transmission; extracellular; frontier; improved; in vivo; mutant; nuclear factors of activated T-cells; receptor; response; single-cell RNA sequencing; transcription factor; transcriptome sequencing; transcriptomics; vaccine delivery; vaccine efficacy

T follicular helper (TFH) cells are essential for establishing protective immunity in responses to infection and immunization, where they help high-affinity antibody production by germinal center (GC) B cells, generation of plasma cells and memory B cells. The TFH-B cell cooperativity thus constitutes the cornerstone of immunological memory formation induced by vaccines. Deciphering pathways and factors that promote TFH cell differentiation and function is a prerequisite for formulating more efficacious vaccines. In response to infection or immunization, activated CD4+ T cells undergo stage-wise differentiation to become functionally competent TFH cells. These stages include early stage TFH lineage specification to generate nascent TFH cells, GC response stage to mature to GC-TFH cells, and later stage formation of memory TFH cells. Vaccines are delivered as live-attenuated viruses, inactivated organisms, or protein subcomponents via different routes. It has not drawn enough attention whether all TFH cells are created equal by different vaccination approaches. We extended our in vivo studies to CD28 and ICOS costimulatory receptors, which are well-established TFH regulators. CD28-PYAP and ICOS-YMFM intracellular motifs are preferentially connected to PKCq/PDK1 and PI3K-Akt pathways, respectively. Current views hold that CD28 is critical for initiating and ICOS for sustaining TFH responses. Contrary to this belief, our preliminary data revealed that the ICOS-YMFM motif is essential for initiating Imm_TFH, while the CD28-PYAP motif was indispensable for sustaining Inf_TFH responses. These findings led to our central hypothesis that TFH cells have distinct molecular requirements depending on activating agents/approaches, where CD28 and ICOS motifs differentially regulate Inf_TFH and Imm_TFH cells in a stage-specific manner. To test this, we designed multi-layered functional and molecular studies in 3 specific aims: Specific Aim 1. To define differential requirements for CD28 and ICOS motifs in TFH fate specification. Specific Aim 2. To delineate CD28 and ICOS motif-controlled molecular circuits that promote GC-TFH cell maturation and B-cell help function. Specific Aim 3. To investigate the roles of CD28 and ICOS motifs in memory TFH persistence and recall response. Developing efficacious vaccines against infectious diseases is thus essential for protecting troops in service as well as veterans. Our proposed study directly addresses this need, by advancing the understanding of TFH cells at new frontiers. We expect to yield essential information on tailoring TFH activity to provide optimal B cell help, and hence provide paradigm-shifting rationales for enhancing vaccine design.

滤泡辅助 T (TFH) 细胞对于建立应对感染的保护性免疫至关重要 和免疫，它们帮助生发中心 (GC) B 细胞产生高亲和力抗体， 浆细胞和记忆B细胞的产生。因此，TFH-B 细胞协同性构成了 疫苗诱导的免疫记忆形成。破译促进 TFH 细胞的途径和因素 分化和功能是配制更有效疫苗的先决条件。 为了响应感染或免疫，激活的 CD4+ T 细胞经历阶段性分化， 成为有功能的TFH细胞。这些阶段包括早期阶段 TFH 谱系规范 生成新生TFH细胞，GC反应阶段成熟为GC-TFH细胞，以及后期记忆形成 TFH 细胞。疫苗以减毒活病毒、灭活生物体或蛋白质亚成分的形式提供 通过不同的路线。所有 TFH 细胞是否都是由不同的细胞产生的，这一点尚未引起足够的重视。 疫苗接种方法。 我们将体内研究扩展到 CD28 和 ICOS 共刺激受体，这些受体都是公认的 TFH 监管机构。 CD28-PYAP 和 ICOS-YMFM 细胞内基序优先与 PKCq/PDK1 连接 和 PI3K-Akt 途径。目前的观点认为，CD28 对于发起至关重要，ICOS 对于发起至关重要。 维持 TFH 应对措施。与这一信念相反，我们的初步数据显示 ICOS-YMFM 主题是 对于启动 Imm_TFH 至关重要，而 CD28-PYAP 基序对于维持 Inf_TFH 是必不可少的 回应。这些发现引出了我们的中心假设：TFH 细胞具有独特的分子特征。 要求取决于激活剂/方法，其中 CD28 和 ICOS 基序有所不同 以特定阶段的方式调节 Inf_TFH 和 Imm_TFH 细胞。为了测试这一点，我们设计了多层 功能和分子研究有 3 个具体目标： 具体目标 1. 定义 TFH 命运规范中 CD28 和 ICOS 基序的差异要求。 具体目标 2. 描绘促进 GC-TFH 的 CD28 和 ICOS 基序控制的分子电路 细胞成熟和 B 细胞帮助发挥功能。 具体目标 3. 研究 CD28 和 ICOS 基序在记忆 TFH 持久性和回忆中的作用 回复。 因此，开发针对传染病的有效疫苗对于保护军队至关重要 服务以及退伍军人。我们提出的研究通过增进理解直接解决了这一需求 TFH 细胞的新领域。我们期望获得有关定制 TFH 活动的重要信息，以提供最佳的 B 细胞提供帮助，从而为增强疫苗设计提供了范式转变的基本原理。