J Immunol. 2025 Aug 7:vkaf160. doi: 10.1093/jimmun/vkaf160. Online ahead of print.
ABSTRACT
The germinal center (GC) reaction is essential for generating high-quality humoral memory. Positively selected GC B cells must decide whether to remain in the GC for further affinity maturation or differentiate into memory or plasma cells (PCs). Previously, we identified IL-21R and CD40 signaling as critical promoters of GC B cell effector differentiation. However, the mechanisms regulating the strength of these signals remain unclear. PTEN, a negative regulator of PI3K signaling, is markedly upregulated in GC B cells. To explore the role of PTEN in GC B cell fate decisions, we used a tamoxifen-driven Cre system to delete PTEN in B cells after GC reaction was fully established. We found that PTEN deletion in ongoing GC B cells led to significantly increased differentiation into PCs, while having limited effects on class switching or memory precursor differentiation. These results were further confirmed using a GC B cell transfer system, where wild-type and PTEN-deficient GC B cells were transferred into the same recipient mice. Mechanistically, PTEN deletion or inhibition in established GC B cells resulted in more sustained IL-21R signaling and enhanced CD40 signaling-both known to promote PC differentiation. Interestingly, Peyer’s patch GC B cells exhibited higher PTEN levels than de novo GC B cells generated through immunization. Notably, PTEN deficiency selectively expanded GC B cells in Peyer’s patches but had no impact on those induced by immunization. These findings reveal previously unrecognized roles for PTEN in regulating GC B cell signaling and limiting their differentiation into PCs.
PMID:40795247 | DOI:10.1093/jimmun/vkaf160