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

> **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $198,125

## Abstract

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

## Key facts

- **NIH application ID:** 10875634
- **Project number:** 5R21AI175824-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Wei Luo
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $198,125
- **Award type:** 5
- **Project period:** 2023-06-26 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875634

## Citation

> US National Institutes of Health, RePORTER application 10875634, The role of PTEN signaling in regulating germinal center B cell fate decision (5R21AI175824-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10875634. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*