Germinal centers (GCs) are sites at which B cells proliferate and mutate their antibody-encoding genes in the dark zone (DZ), followed by affinity-based selection in the light zone (LZ). B cell antigen receptor (BCR) signals induce Syk activation followed by rapid phosphatase-mediated desensitization; however, how degradation events regulate BCR functions in GCs is unclear. Here, we found that Syk degradation restrains plasma cell (PC) formation in GCs and promotes B cell LZ to DZ transition. Using a mouse model defective in Cbl-mediated Syk degradation, we demonstrate that this machinery attenuates BCR signaling intensity by mitigating the Kras/Erk and PI3K/Foxo1 pathways, and restricting the expression of PC transcription factors in GC B cells. Inhibition of Syk degradation perturbed gene expression, specifically in the LZ, and enhanced the generation of PCs without affecting B cell proliferation. These findings reveal how long-lasting attenuation of signal transduction by degradation events regulates cell fate within specialized microanatomical sites.
Syk degradation restrains plasma cell formation and promotes zonal transitions in germinal centers
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Natalia Davidzohn, Adi Biram, Liat Stoler-Barak, Amalie Grenov, Bareket Dassa, Ziv Shulman; Syk degradation restrains plasma cell formation and promotes zonal transitions in germinal centers. J Exp Med 2 March 2020; 217 (3): e20191043. doi: https://doi.org/10.1084/jem.20191043
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