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