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: 10367461
• 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/10367461
• 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; Complement; Data; Disease; Funding; Gene Expression Regulation; Generations; Genetic; Genetic Transcription; Genome; Genomics; Helper-Inducer T-Lymphocyte; Immunity; Immunization; Immunologic Memory; Infection; Knowledge; LoxP-flanked allele; Memory; Memory B-Lymphocyte; Military Personnel; Molecular; Mutant Strains Mice; Mutation; Nuclear; Organism; Output; PDPK1 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; Tumor stage; Vaccination; Vaccine Design; Vaccines; Veterans; Viral Proteins; Virus; Virus Diseases; acute infection; design; extracellular; frontier; improved; in vivo; mutant; 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.

T滤泡辅助细胞(TFH)是在感染反应中建立保护性免疫所必需的 以及免疫，它们帮助生发中心(GC)B细胞产生高亲和力抗体， 产生浆细胞和记忆B细胞。因此，TFH-B细胞的协同性构成了 疫苗诱导的免疫记忆形成。促进TFH细胞的破译途径和因素 分化和功能是研制出更有效疫苗的前提。 作为对感染或免疫的反应，激活的CD4+T细胞经历阶段分化，以 成为功能正常的TFH细胞。这些阶段包括早期TFH谱系规范到 产生新生的TFH细胞，GC反应期成熟到GC-TFH细胞，以及后期记忆的形成 TFH细胞。疫苗以减毒活病毒、灭活生物体或蛋白亚组分的形式提供。 通过不同的路线。是否所有的TFH细胞都是由不同的细胞平等产生的，还没有引起足够的关注 疫苗接种即将到来。 我们将体内研究扩展到CD28和ICOS共刺激受体，这两种受体是公认的 TFH监管机构。CD28-PYAP和ICOS-YMFM胞内基序优先与PKCq/PDK1连接 和PI3K-Akt通路。目前的观点认为，CD28对于启动和ICOS对于 持续的TFH反应。与这种看法相反，我们的初步数据显示，ICOS-YMFM基序是 CD28-PYAP基序对于启动IMM_TFH是必不可少的，而CD28-PYAP基序对于维持inf_TFH是必不可少的 回应。这些发现导致了我们的中心假设，即TFH细胞具有不同的分子 要求取决于激活剂/方法，其中CD28和ICOS主题不同 以阶段特异性的方式调节inf_TFH和imm_TFH细胞。为了测试这一点，我们设计了多层 三个特定目标的功能和分子研究： 具体目标1.在TFH FATE规范中定义CD28和ICOS基序的不同要求。 特定目的2.描绘CD28和ICOS基序控制的促进GC-TFH的分子回路 细胞成熟和B细胞的辅助功能。 具体目的3.研究CD28和ICOS基序在记忆、TFH持续和回忆中的作用 回应。 因此，开发有效的传染病疫苗对于保护驻阿富汗部队至关重要。 无论是退伍军人还是现役军人。我们提出的研究直接满足了这一需求，通过促进对 TFH细胞在新的边界。我们期望得到关于调整TFH活动的基本信息，以提供最佳的 B细胞有帮助，因此为加强疫苗设计提供了范式转换的理论基础。