Restriction of memory B cell differentiation at the germinal center B cell positive selection stage

Toboso-Navasa, Amparo; Gunawan, Arief; Morlino, Giulia; Nakagawa, Rinako; Taddei, Andrea; Damry, Djamil; Patel, Yash D.; Chakravarty, Probir; Janz, Martin; Kassiotis, George; Brink, Robert; Eilers, Martin; Calado, Dinis Pedro

doi:10.1084/jem.20191933

Cited by 27 publications

(27 citation statements)

References 104 publications

(182 reference statements)

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“…For the MBC fate decision in cMyc + GC B cells, coexpression of cMyc-interacting proteins perhaps plays a key role. We recently discovered that cMyc binds to the transcription factor MIZ1 to restrict positively selected GC B cells from forming MBCs and favor expansion of GC B cells ( 57 ). Hhex, an important transcription factor for MBC differentiation ( 51 ), can interact with cMyc to decrease its activity, including cell proliferation and metabolism in tumors ( 58 ).…”

Section: Discussionmentioning

confidence: 99%

Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth

Nakagawa

Toboso-Navasa

Schips

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Affinity maturation depends on how efficiently germinal centers (GCs) positively select B cells in the light zone (LZ). Positively selected GC B cells recirculate between LZs and dark zones (DZs) and ultimately differentiate into plasmablasts (PBs) and memory B cells (MBCs). Current understanding of the GC reaction presumes that cMyc-dependent positive selection of LZ B cells is a competitive affinity-dependent process; however, this cannot explain the production of GC-derived lower-affinity MBCs or retention of GC B cells with varied affinities. Here, by combining single-cell/bulk RNA sequencing and flow cytometry, we identified and characterized temporally and functionally distinct positively selected cMyc+ GC B cell subpopulations. cMyc+ LZ B cell subpopulations enriched with either higher- or lower-affinity cells diverged soon after permissive positive selection. The former subpopulation contained PB precursors, whereas the latter comprised less proliferative MBC precursors and future DZ entrants. The overall affinity of future DZ entrants was enhanced in the LZ through preferential proliferation of higher-affinity cells. Concurrently, lower-affinity cells were retained in GCs and protected from apoptosis. These findings redefine positive selection as a dynamic process generating three distinct B cell fates and elucidate how positive selection ensures clonal diversity for broad protection.

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Section: Discussionmentioning

confidence: 99%

Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth

Nakagawa

Toboso-Navasa

Schips

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…MYC regulates multiple aspects of cell proliferation including metabolism and the expression of proteins that are necessary to sustain cell division, such as activating enhancer binding protein 4 (AP4; also known as TFAP4) and ubiquitin-like, containing PHD and RING finger domains, 1 (UHRF1) 89,90 . MYC interacts with the transcriptional activator MYC-interacting zinc finger protein 1 (MIZ1) to form a transcriptional repressor complex that represses MIZ1 target genes 91 . The MYC-MIZ1 complex promotes cell cycle entry of GC B cells actively receiving T cell help 91 .…”

Section: Box 2 | Memory B Cell Subsetsmentioning

confidence: 99%

“…MYC interacts with the transcriptional activator MYC-interacting zinc finger protein 1 (MIZ1) to form a transcriptional repressor complex that represses MIZ1 target genes 91 . The MYC-MIZ1 complex promotes cell cycle entry of GC B cells actively receiving T cell help 91 . Whereas MYC is rapidly downregulated in GC B cells that enter the dark zone, AP4 expression is maintained and is necessary for dark zone B cells to undergo continued cell division 92 .…”

Section: Box 2 | Memory B Cell Subsetsmentioning

confidence: 99%

“…These cells also fail to express MYC, which is required for both the accumulation of metabolites necessary for cell division and for entry into the cell cycle 89 . MYC functions in complex with MIZ1 to promote plasma cell development and restrict MBC differentiation 91 . GC B cells that receive low levels of T cell help also maintain elevated BACH2 expression, perhaps owing to reduced repression of BACH2 transcription by mTORC1 (refs 103 , 106 ).…”

Section: Regulation Of Mbc Differentiationmentioning

confidence: 99%

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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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“…For the MBC fate instruction, interplay between transcription factors exerts functions that regulate MBC differentiation from cMyc + GC-B cells. Myc-interacting zinc finger protein-1 (MIZ-1) is expressed in most cMyc + LZ-B cells and the transcriptional activator Miz-1 switches to a transcriptional repressor upon cMyc binding ( 94 , 95 ). The cMyc/Miz-1 complex represses Miz-1 target genes and results in restricting positively selected GC-B cells from forming MBCs to favor GC-B cell fate as DZ-entrants ( 94 ).…”

Section: Molecular Events During Positive Selection and B Cell Fate Imentioning

confidence: 99%

Positive Selection in the Light Zone of Germinal Centers

Nakagawa

Calado

2021

Front. Immunol.

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Germinal centers (GCs) are essential sites for the production of high-affinity antibody secreting plasma cells (PCs) and memory-B cells (MBCs), which form the framework of vaccination. Affinity maturation and permissive selection in GCs are key for the production of PCs and MBCs, respectively. For these purposes, GCs positively select “fit” cells in the light zone of the GC and instructs them for one of three known B cell fates: PCs, MBCs and persistent GC-B cells as dark zone entrants. In this review, we provide an overview of the positive selection process and discuss its mechanisms and how B cell fates are instructed.

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Restriction of memory B cell differentiation at the germinal center B cell positive selection stage

Cited by 27 publications

References 104 publications

Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth

Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth

Transcriptional regulation of memory B cell differentiation

Positive Selection in the Light Zone of Germinal Centers

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