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

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 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响应可能会导致 导致自身免疫或过敏性疾病的有害抗体的产生。迫切需要 治疗性地操纵GC反应以提高疫苗的效力以及有效地治疗疾病 由致病的B细胞记忆形成引起。实现这一目标的一个障碍是缺乏对 正选择后调控GC B细胞(GCBC)命运的机制。最重要的是，信号 能够引导GC B细胞分化为记忆隔间而不是在GC内循环的方法仍然很差 明白了。磷酸酶和张力蛋白同源蛋白(PTEN)在GCBC中的表达高度升高，导致 在一个独特的AKT信令网络中。PTEN缺乏症损害B细胞耐受性并损害类别转换 GC中的重组。然而，关于PTEN信号在GCBC命运决定中的作用，人们知之甚少。我们 已经产生了耐人寻味的初步数据，表明在已建立的GCBC中敲除PTEN增强了 他们对PC的分化。这项建议的目的是进一步阐明细胞的分子调控 PTEN信号调控的GCBC命运决定。我们的总体假设是GCBC的命运决定是受调控的 通过PTEN信号的强弱和强T辅助信号下调PTEN信号在GCBC中的促进作用 它们分化成记忆隔间。这一假设将通过两个目的进行检验：1)阐明 PTEN信号如何控制GCBC命运的机制。我们假设PTEN单倍体功能不全 在GCBC中，PTEN的完全缺失有利于MBC的分化，而PTEN的完全缺失则有利于PC的分化。2)确定 GCBC中调节PTEN的信号通路。我们的假设是，强烈的T辅助信号可以下调 PTEN通过持续的c-Myc表达而在GCBC中表达。在完成这些研究后，我们预计会产生 了解PTEN信号在GCBC命运决定中的作用和调控。这个 从这些研究中获得的机械性见解可能会为控制GC反应开辟新的途径 操纵PTEN信号网络，有可能提高疫苗效力并开发新的 治疗与致病性GC反应相关的疾病。 1

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