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) 反应产生记忆 B 细胞 (MBC) 和长寿浆细胞 (PC)，它们是 对于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 产生导致自身免疫或过敏性疾病的有害抗体。迫切需要 治疗性操纵 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。实现这一目标的一个障碍是缺乏对 正选择后调节 GC B 细胞 (GCBC) 命运决定的机制。最重要的是，信号 能够引导 GC B 细胞分化为记忆室而不是在 GC 内回收的方法仍然很差 明白了。磷酸酶和张力蛋白同源物 (PTEN) 蛋白表达在 GCBC 中高度升高，导致 位于独特的 AKT 信号网络中。 PTEN 缺陷会损害 B 细胞耐受性并损害类别转换 GC 中的重组。然而，人们对 PTEN 信号在 GCBC 命运决定中的作用知之甚少。我们 已经产生了有趣的初步数据，表明敲除已建立的 GCBC 中的 PTEN 增强 他们对 PC 的差异化。该提案的目的是进一步阐明其分子调控 GCBC 命运决定由 PTEN 信号控制。我们的总体假设是 GCBC 命运决定受到监管 通过 PTEN 信号强度，强 T 辅助信号下调 GCBC 中的 PTEN 信号，从而促进 它们分化成记忆区。该假设将通过两个目标进行检验：1）阐明 PTEN 信号如何控制 GCBC 命运决定的机制。我们假设 PTEN 单倍体不足 GCBC 中的 GCBC 将有利于 MBC 分化，而 PTEN 的完全删除将有利于 PC 分化。 2) 识别 GCBC 中调节 PTEN 的信号通路。我们的假设是强 T 辅助信号可以下调 GCBC 中的 PTEN 通过持续的 c-Myc 表达。完成这些研究后，我们期望产生 关于 PTEN 信号在 GCBC 命运决定中的功能和调节的关键知识。这 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 响应 操纵 PTEN 信号网络，有可能提高疫苗功效并开发新的疫苗 治疗与致病性GC反应相关的疾病。 1