PTEN controls IL-21R signaling and germinal center B cell effector differentiation toward plasma cells 2943

Description The germinal center (GC) reaction is crucial for generating high-quality humoral memory. Our previous research showed that GC B cells express higher levels of the PTEN protein compared to naïve B cells, which contributes to reprogramming B cell receptor (BCR) signaling within GC B cells. PTEN, a key negative regulator of PI3K signaling, plays a critical role in B cell development and class switching during antibody responses. However, its specific role in regulating established GC B cells remains unclear. To explore this, we used a tamoxifen-inducible Cre system to delete PTEN in B cells during the peak of the GC response. We found that PTEN deletion in ongoing GC B cells led to significantly increased differentiation into plasma cells (PCs), while having a minimal effect on class switching or memory precursor differentiation. These results were further confirmed through a GC B cell transfer system, where both wild-type and PTEN-deficient GC B cells were transferred into the same host mice. Mechanistically, we found that PTEN deletion or pharmacologic inhibition in established GC B cells resulted in more sustained IL-21R signaling and enhanced CD40 signaling. These two signals together are known to promote GC B cell differentiation into PCs. These findings reveal previously unrecognized roles for PTEN in regulating GC B cell signaling downstream of both IL-21R and CD40, thereby limiting their differentiation into PCs. Funding Sources Supported by NIH grants R21AI175824; R01AI184891; Supported by the Indiana Clinical and Translational Sciences Institute funded, in part by Grant Number UM1TR004402 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award.