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

生发中心（GC）响应生成记忆B细胞（MBC）和长寿命的浆细胞（PC）， 我们对病原体感染和疫苗接种的免疫反应至关重要。不受控制的GC响应可能会导致 导致自身免疫性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反应以提高疫苗功效，并有效治疗疾病 由致病性B细胞记忆形成引起。实现这一目标的障碍是对 调节GC B细胞（GCBC）命运决策的机制在阳性选择后。最重要的是，信号传导 可以指导GC B细胞分化为存储室而不是在GC内回收的隔室很差 理解。 GCBC中的磷酸酶和Tensin同源物（PTEN）蛋白表达高度升高，导致 在唯一的AKT信号网络中。 PTEN缺乏症会损害B细胞的耐受性并损害类转换 GC中的重组。但是，对于PTEN信号在GCBC命运决策中的作用知之甚少。我们 已经产生了有趣的初步数据，表明在已建立的GCBC中拆除PTEN 它们对PC的区分。该提议的目的是进一步阐明 GCBC命运决定由PTEN信号控制。我们的总体假设是GCBC命运决策受到调节 通过PTEN信号强度和强大的T辅助信号在GCBC中下调PTEN信号传导以促进 它们分化为存储室。该假设将通过两个目的进行检验：1）阐明 PTEN信号如何控制GCBC命运决策的机制。我们假设PTEN单倍度不足 在GCBC中，将有利于MBC差异化，而PTEN的完全删除将有利于PC差异化。 2）确定 信号通路调节GCBC中的PTEN。我们的假设是强大的T辅助信号可以下调 通过持续的C-MYC表达在GCBC中进行PTEN。完成这些研究后，我们希望产生 关于GCBC命运决策中PTEN信号的功能和调节的关键知识。这 从这些研究中获得的机械洞察力可能会开辟新的途径，以通过 操纵PTEN信号网络，该网络有可能提高疫苗功效并发展新颖 与致病性GC反应有关的疾病治疗。 1