Germinal centers: a game of clones in immunological niches

Establishment of effective immunity against invading microbes depends on the continuous generation of antibodies that facilitate pathogen clearance and long lasting immunity. Generation of antibody-forming cells takes place within lymphoid organs where B cells interact with various types of immune cells that promote proliferation and selection of high-affinity antibodies within specialized microanatomical sites known as germinal centers. Germinal centers are sites at which B cells proliferate and mutate their antibody-encoding genes in the dark-zone, followed by affinity-based selection in the light-zone. How do interactions between different immune cell types within germinal centers and triggering of intracellular signaling events generate long lasting immunity remains unclear. B cell antigen receptor signals induce Syk activation followed by rapid phosphatase-mediated desensitization; however, how degradation events regulate immune-receptor functions in germinal centers is unknown. We demonstrate that Syk proteasomal degradation restrains antibody-forming cells formation in germinal centers and promotes B cell zonal transitions. Using a mouse model defective in Cbl-mediated Syk degradation, we demonstrate that this machinery attenuates immune-receptor signaling intensity by mitigating the Kras/Erk and PI3K/Foxo1 pathways, and restricting expression of the antibody-forming cell transcription factors, Irf4 and Blimp-1. Inhibition of Syk degradation perturbed gene expression, specifically in the light zone, and enhanced generation of antibody-forming cells without affecting B cell proliferation. These findings reveal how long-lasting attenuation of signal transduction by degradation events regulate cell fate within specialized microanatomical sites.