The role of PTEN signaling in regulating germinal center B cell fate decision

PTEN信号在调节生发中心B细胞命运决定中的作用

• 批准号: 10646533
• 负责人: Wei Luo
• 金额: $ 23.78万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-26 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646533
• 关键词: Adoptive Transfer; Affect; Affinity; Allergic Disease; Antibodies; Autoimmune Diseases; Autoimmunity; B cell differentiation; B-Cell Development; B-Lymphocytes; Biological Process; Bone Marrow; CD19 gene; Cell Communication; Cells; Coupled; Data; Development; Disease; Down-Regulation; Enterobacteria phage P1 Cre recombinase; FRAP1 gene; Face; Generations; Genes; Goals; Homologous Protein; Hypersensitivity; Immune response; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin Switch Recombination; Immunologic Memory; Impairment; Infection; Inositol; Knowledge; Lipids; Maintenance; Memory; Memory B-Lymphocyte; Metabolism; Molecular; PIK3CG gene; PTEN gene; Pathogenicity; Pathway interactions; Plasma Cells; Proto-Oncogene Proteins c-akt; Public Health; Reaction; Recycling; Regulation; Role; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; System; Testing; Therapeutic; Vaccination; activation-induced cytidine deaminase; anergy; c-myc Genes; improved; in vivo; inducible Cre; insight; knock-down; novel; novel strategies; pathogen; plasma cell differentiation; prevent; protein expression; response; transcriptomics; vaccine efficacy

Germinal center (GC) response generates memory B cells (MBC) and long-lived plasma cells (PC), which are critical in our immune responses to pathogen infection and vaccination. Uncontrolled GC response may result in the development of harmful antibodies that cause autoimmunity or allergic diseases. There is a critical need to therapeutically manipulate GC response to improve vaccine efficacy as well as to effectively treat diseases caused by pathogenic B cell memory formation. A barrier to achieving this is a lack of understanding of mechanisms regulating GC B cell (GCBC) fate decision post positive selection. Most importantly, the signaling that can guide GC B cells to differentiate into memory compartments instead of recycling within GC is still poorly understood. Phosphatase and tensin homolog (PTEN) protein expression is highly elevated in GCBC, resulting in a unique AKT signaling network. PTEN deficiency compromises B cell tolerance and impairs class-switching recombination in the GC. However, little is known about the role of PTEN signaling in GCBC fate decision. We have generated intriguing preliminary data showing that knocking down PTEN in established GCBC enhanced their differentiation toward PC. The objective of this proposal is to further elucidate the molecular regulation of GCBC fate decision controlled by PTEN signaling. Our overall hypothesis is that GCBC fate decision is regulated by PTEN signaling strength, and strong T helper signals down-regulate PTEN signaling in GCBC to promote their differentiation into the memory compartments. This hypothesis will be tested via two aims: 1) Elucidate the mechanisms of how PTEN signaling controls GCBC fate decision. We hypothesize that PTEN haploinsufficiency in GCBC will favor MBC differentiation while full deletion of PTEN will favor PC differentiation. 2) Identify the signaling pathways regulating PTEN in GCBC. Our hypothesis is that strong T helper signals can downregulated PTEN in GCBC through sustained c-Myc expression. Upon completion of these studies, we expect to generate key knowledge regarding both the function and regulation of PTEN signaling in GCBC fate decision. The mechanistic insights achieved from these studies may open new avenues to control GC response through manipulating PTEN signaling network, which has the potential to improve vaccine efficacy and to develop novel treatments for diseases related to pathogenic GC response. 1

老年中心（GC）反应产生记忆B细胞（MBC）和长寿浆细胞（PC），它们是 在我们对病原体感染和疫苗接种的免疫反应中至关重要。不受控制的GC反应可能导致 导致自身免疫或过敏性疾病的有害抗体的发展。迫切需要 在治疗上操纵GC应答以提高疫苗效力以及有效治疗疾病 由致病性B细胞记忆形成引起。实现这一目标的一个障碍是缺乏对 调节GC B细胞（GCBC）命运决定的机制。最重要的是， 能够引导GC B细胞分化为记忆区室，而不是在GC内循环的基因仍然很差， 明白磷酸酶和张力蛋白同源物（PTEN）蛋白表达在GCBC中高度升高， 在唯一的AKT信令网络中。PTEN缺陷损害B细胞耐受性并损害类别转换 在GC中重组。然而，很少有人知道在GCBC的命运决定的PTEN信号转导的作用。我们 已经产生了有趣的初步数据，显示在建立的GCBC中敲除PTEN可以增强 与PC的区别。该建议的目的是进一步阐明 GCBC命运决定由PTEN信号传导控制。我们的总体假设是，GCBC的命运决定是受调节的， 通过PTEN信号强度，强T辅助信号下调GCBC中的PTEN信号， 它们分化成记忆隔间。这一假设将通过两个目标进行测试：1）阐明 PTEN信号如何控制GCBC命运决定的机制。我们假设PTEN单倍不足 在GCBC中，PTEN的完全缺失将有利于MBC分化，而PTEN的完全缺失将有利于PC分化。2)识别 GCBC中调节PTEN的信号通路。我们的假设是，强烈的辅助性T细胞信号可以下调， 通过持续的c-Myc表达在GCBC中的PTEN。在完成这些研究后，我们预计 关于GCBC命运决定中PTEN信号传导的功能和调节的关键知识。的 从这些研究中获得的机制见解可能会开辟新的途径来控制GC反应， 操纵PTEN信号网络，这有可能提高疫苗的效力，并开发新的 治疗与致病性GC反应相关的疾病。 1