TGFβ signaling in germinal center B cells promotes the transition from light zone to dark zone

Albright, Anne R.; Kabát, Juraj; Li, Moyi; Raso, Fiona; Reboldi, Andrea; Muppidi, Jagan R.

doi:10.1084/jem.20181868

Cited by 30 publications

(22 citation statements)

References 34 publications

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“…FOXO1 regulates the expression of numerous genes, including Cxcr4 , which encode a G-protein-coupled receptor necessary for migration of B cells to the dark zone 82 , 84 . Transforming growth factor-β (TGFβ) and IL-10 signalling in GC B cells promote FOXO1 expression 85 , 86 . The transcriptional programme regulated by FOXO1 largely overlaps with that of BCL-6, suggesting that FOXO1 and BCL-6 cooperate to support the dark zone state 82 .…”

Section: Regulation Of Gc B Cell Maintenancementioning

confidence: 99%

Transcriptional regulation of memory B cell differentiation

2020

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During an immune response, B cells that encounter their cognate antigen become activated and differentiate to form short-lived antibody-secreting cells or germinal centre (GC)-independent memory B cells (MBCs). Within the GC, B cells engage with antigen and compete for limiting amounts of T cell help, which is necessary for B cell survival, proliferation and eventual differentiation into plasma cells or GC-derived MBCs 1. The GC is also the primary site in which B cells undergo somatic hypermutation, with B cells that accrue productive mutations preferentially receiving T cell help. The GC response is required for the development of affinity-matured plasma cells and MBCs (Box 1). MBCs are an important component of protective immunity. MBCs are distinguished by their capacity to survive long term and to rapidly differentiate into antibody-secreting cells upon antigen re-encounter. MBCs can also re-enter the GC during recall responses, where they undergo further somatic hypermutation 2-5. MBCs tend to emerge from the GC during the early phases of the GC response and typically display reduced levels of somatic hypermutation and affinity maturation relative to plasma cells 6-8. In the context of viral infections, the reduced mutational load of MBCs allows these cells to maintain enhanced flexibility in their responsiveness to different viral subtypes compared with plasma cells, which tend to be specific for a particular subtype. Indeed, the MBC population contains an elevated fraction of broadly reactive clones relative to the plasma cell pool for numerous pathogens in both mice and humans 9-12. The MBC response comprises multiple subsets, identified based on their expression of CD80 and PDL2, among other markers 5,8 (Box 2). These MBC subsets emerge from the GC at different times and vary in their capacity to re-enter the GC or differentiate into antibody-secreting cells upon antigen re-encounter 5,6. Iterative exposure to cross-reactive viral antigens is an emerging vaccination strategy designed to elicit broadly reactive MBCs capable of mediating heterosubtypic immunity against pathogens such as influenza. The potential efficacy of an iterative vaccination strategy is limited by the relative inefficiency with which most MBC clones re-enter the GC response 13-15. The secondary GC response tends to consist largely of recently activated naive B cells, with only certain MBC subsets possessing the capacity to efficiently re-enter the GC 4,5,16. Currently, it is unclear why the majority of MBCs fail to participate in secondary GC responses. One possibility is that antigen-specific antibodies limit the ability of MBC clones of the same specificity to access antigen and participate in the GC response 4,17. MBCs can arise through both GC-dependent and GC-independent pathways 18-20. GC-independent MBCs largely develop during the early stages of the immune response and contribute to protective immunity against numerous pathogens including Ehrlichia muris and malaria 14,21. GC-independent MBCs can be somatically hypermutated ...

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Section: Regulation Of Gc B Cell Maintenancementioning

confidence: 99%

Transcriptional regulation of memory B cell differentiation

2020

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“…In addition, we detected lower levels of FOXO1 protein known to accompany its phosphorylation upon gating either total GC B cells or LZ B cells (Supplemental Figure 6, C and D, and ref. 44). Thus, ROCK2 promotes FOXO1 activation and controls a FOXO1-repressed gene set in GC B cells, probably through its ability to regulate AKT activity.…”

Section: Rock2 Induces Expression Of the Cholesterol Biosynthesis Patmentioning

confidence: 99%

Serine-threonine kinase ROCK2 regulates germinal center B cell positioning and cholesterol biosynthesis

Ricker¹,

Chinenov²,

Pannellini³

et al. 2020

Journal of Clinical Investigation

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“…Transforming growth factor (TGF)-β signaling is involved in several processes regulating B cell maturation. For instance, a study showed that IgD+ B cells were observed in the presence of TGF-β signaling, whereas genetic deletion of the receptor led to complete loss of IgD ( Albright et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

TGFβ signaling in germinal center B cells promotes the transition from light zone to dark zone

Cited by 30 publications

References 34 publications

Transcriptional regulation of memory B cell differentiation

Transcriptional regulation of memory B cell differentiation

Serine-threonine kinase ROCK2 regulates germinal center B cell positioning and cholesterol biosynthesis

Dual data and motif clustering improves the modeling and interpretation of phosphoproteomic data

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