In mucosal lymphoid tissue such as Peyer’s patches (PPs) and mesenteric LNs (mLNs), GCs are thought to form in response to chronic stimulation by microbial products and other stimuli derived from the gut ( Fagarasan et al., 2010 Reboldi and Cyster, 2016). While BCR signaling has been implicated in inducing the phosphorylation of Foxo1, the cues in the GC microenvironment that might induce dephosphorylation and nuclear translocation of Foxo1 in LZ cells and allow for transition to the DZ state have not been defined ( Cyster, 2015 Luo et al., 2018).
A fraction of LZ GCBs show active nuclear Foxo1, and these cells are thought to be in the process of transitioning to the DZ ( Sander et al., 2015). In the LZ, Foxo1 is phosphorylated (p), preventing it from entering the nucleus and targeting it for degradation. Foxo1 was shown to be more active in DZ GCBs. Recent work has demonstrated that the transcription factor forkhead box protein O1 (Foxo1) is required for GCBs to maintain the DZ state ( Dominguez-Sola et al., 2015 Sander et al., 2015 Inoue et al., 2017). Iterative cycling of GC B cells (GCBs) between LZ and DZ allows for the generation of B cells expressing high-affinity BCR. B cells in GCs cycle between the light zone (LZ), where they can receive T cell help on the basis of their ability to acquire antigen via their B cell receptor (BCR), and the dark zone (DZ), where they proliferate and undergo somatic hypermutation of their BCR ( Victora and Nussenzweig, 2012). Germinal centers (GCs) form in secondary lymphoid organs following immunization and after infection and are necessary for humoral immunity to pathogens ( Victora and Nussenzweig, 2012).
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