scholarly journals Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation

2006 ◽  
Vol 203 (4) ◽  
pp. 1081-1091 ◽  
Author(s):  
Didrik Paus ◽  
Tri Giang Phan ◽  
Tyani D. Chan ◽  
Sandra Gardam ◽  
Antony Basten ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Germinal Center ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
B Cell Differentiation ◽  
High Affinity ◽  
Germinal Center B Cell

B cells responding to T-dependent antigen either differentiate rapidly into extrafollicular plasma cells or enter germinal centers and undergo somatic hypermutation and affinity maturation. However, the physiological cues that direct B cell differentiation down one pathway versus the other are unknown. Here we show that the strength of the initial interaction between B cell receptor (BCR) and antigen is a primary determinant of this decision. B cells expressing a defined BCR specificity for hen egg lysozyme (HEL) were challenged with sheep red blood cell conjugates of a series of recombinant mutant HEL proteins engineered to bind this BCR over a 10,000-fold affinity range. Decreasing either initial BCR affinity or antigen density was found to selectively remove the extrafollicular plasma cell response but leave the germinal center response intact. Moreover, analysis of competing B cells revealed that high affinity specificities are more prevalent in the extrafollicular plasma cell versus the germinal center B cell response. Thus, the effectiveness of early T-dependent antibody responses is optimized by preferentially steering B cells reactive against either high affinity or abundant epitopes toward extrafollicular plasma cell differentiation. Conversely, responding clones with weaker antigen reactivity are primarily directed to germinal centers where they undergo affinity maturation.

scholarly journals Germinal Centers without T Cells

2000 ◽  
Vol 191 (3) ◽  
pp. 485-494 ◽  
Author(s):  
Carola García de Vinuesa ◽  
Matthew C. Cook ◽  
Jennifer Ball ◽  
Marion Drew ◽  
Yvonne Sunners ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
High Efficiency ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
High Affinity ◽  
Safe Mechanism ◽  
Germinal Center Formation

Germinal centers are critical for affinity maturation of antibody (Ab) responses. This process allows the production of high-efficiency neutralizing Ab that protects against virus infection and bacterial exotoxins. In germinal centers, responding B cells selectively mutate the genes that encode their receptors for antigen. This process can change Ab affinity and specificity. The mutated cells that produce high-affinity Ab are selected to become Ab-forming or memory B cells, whereas cells that have lost affinity or acquired autoreactivity are eliminated. Normally, T cells are critical for germinal center formation and subsequent B cell selection. Both processes involve engagement of CD40 on B cells by T cells. This report describes how high-affinity B cells can be induced to form large germinal centers in response to (4-hydroxy-3-nitrophenyl) acetyl (NP)-Ficoll in the absence of T cells or signaling through CD40 or CD28. This requires extensive cross-linking of the B cell receptors, and a frequency of antigen-specific B cells of at least 1 in 1,000. These germinal centers abort dramatically at the time when mutated high-affinity B cells are normally selected by T cells. Thus, there is a fail-safe mechanism against autoreactivity, even in the event of thymus-independent germinal center formation.

scholarly journals Coupled Antigen and BLIMP1 Asymmetric Division With a Large Segregation Between Daughter Cells Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells and a DZ-to-LZ Ratio in the Germinal Center

2021 ◽  
Vol 12 ◽  
Author(s):  
Elena Merino Tejero ◽  
Danial Lashgari ◽  
Rodrigo García-Valiente ◽  
Jiaojiao He ◽  
Philippe A. Robert ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Germinal Centers ◽  
Memory B Cells ◽  
Plasma Cell Differentiation ◽  
Daughter Cells

Memory B cells and antibody-secreting plasma cells are generated within germinal centers during affinity maturation in which B-cell proliferation, selection, differentiation, and self-renewal play important roles. The mechanisms behind memory B cell and plasma cell differentiation in germinal centers are not well understood. However, it has been suggested that cell fate is (partially) determined by asymmetric cell division, which involves the unequal distribution of cellular components to both daughter cells. To investigate what level and/or probability of asymmetric segregation of several fate determinant molecules, such as the antigen and transcription factors (BCL6, IRF4, and BLIMP1) recapitulates the temporal switch and DZ-to-LZ ratio in the germinal center, we implemented a multiscale model that combines a core gene regulatory network for plasma cell differentiation with a model describing the cellular interactions and dynamics in the germinal center. Our simulations show that BLIMP1 driven plasma cell differentiation together with coupled asymmetric division of antigen and BLIMP1 with a large segregation between the daughter cells results in a germinal center DZ-to-LZ ratio and a temporal switch from memory B cells to plasma cells that have been observed in experiments.

OCT2 (Octamer Binding Protein 2): An Essential Role in Germinal Center B Cell Differentiation and the “Achilles Heel” of Derived Lymphomas.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 362-362 ◽  
Author(s):  
Stella M Ranuncolo ◽  
Vu Ngo ◽  
Georg Lenz ◽  
Wenming Xiao ◽  
George Wright ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Lines ◽  
Germinal Center ◽  
Target Genes ◽  
B Cell Differentiation ◽  
Pou Domain ◽  
Germinal Center B Cell ◽  
Octamer Motif

Abstract Abstract 362 To identify genes requiered for the proliferation and survival of Diffuse Large B Cell Lymphomas (DLBCL) we conducted an “Achilles Heel” RNA interference screen in cell lines model of ABC (Activated B cell-like) and GCB (Germinal Center B-cell like) DLBCL subtypes. One of the most toxic small hairpins RNAs (shRNAs) in this screen targeted Oct2, encoding a POU domain transcriptional activator. Unlike Oct1, which is constitutively expressed in many cell types, Oct2 is primarily lymphoid restricted. It was identified by virtue of its ability to bind the highly conserved DNA octamer motif (ATGCAAAT) within immunoglobulin (Ig) genes promoters. The B cell specific co-activator OCA-B interacts with the POU domain of the octamer binding proteins enhancing their transactivation potential. Although Oct2 and OCA-B are not essential for Ig transcription, they are required for germinal center (GC) B cell differentiation. To understand the massive apoptotic cell death of DLBCL cells following shRNA Oct2 induction we investigated the genetic pathways controlled by Oct2. We profiled gene expression changes in DLBCL cell lines after knocking down Oct2 and merged this data set with data from genome-wide assessment of Oct2 and OCA-B binding sites, coupling chromatin immunoprecipitation (ChiP) with high-throughput sequencing technologies (ChIP-Seq). ChIP-Seq uncovered an extensive network of Oct2 target genes in DLBCL cells. More than 60% of the Oct2 target genes also showed OCA-B biding. This Oct2/OCA-B overlaping set of targets was enriched for genes selectively expressed in pan-B cells and GC B cells. We found that Oct2/OCA-B lie upstream many of the main transcription factors known to play an essential role in inducing and mantaining the GC stage of B cell development such as BCL6, MTA3, PU.1, IRF8, SpiB and OCA-B, among others. Oct2/OCA-B target these genes both in DLBCL cells and in normal human primary centroblasts. Strikingly, among Oct-2 downstream effectors, BCL6 cDNA was enough to rescue both ABC and GCB DLBCL cells from the Oct2 shRNA lethal effect. The Oct2/OCA-B binding of BCL6 promoter was confirmed in vivo by single locus ChIP in different GCB-DLBCL cell lines as well as in primary centroblasts isolated from human tonsils. Gel shifts experiments showed Oct2 binding to more than one non canonical octamer motif within the BCL6 promoter. Furthermore, computational analysis of the BCL6 promoter region bound by Oct2, showed PU.1 binding sites. Knocked down of PU.1 decreased Oct2 enrichment and viceversa suggesting cooperative Oct2/PU.1 biding to BCL6 pomoter. ChIP-Seq findings opened an entire and exciting new chapter in the Oct2 biology field. Pou transcription factors were suppossed to regulate the activity of octamer containing promoters. Interestingly, Oct2 binds to and control the expression of many GC specific genes that do not harbor a “canonical octamer” motif. Eventhough Oct2 is expressed throughout the different stages of B cell maturation, both mRNA and protein levels are enhanced in centroblasts as compared to pre-GC B cells. We found Oct2 capable of inducing its own expression as well as Oct-1 and OCA-B. This autoregulatory circuit might partially account for the Oct2 predominant role in GC specific genes expression control. By array cGH, high level amplification of Oct2 and OCA-B was found in less than 10% of non Hodgkin lymphoma patients samples. Nonetheless, these lymphoma cells become addicted to the Oct2 controlled network that sustain cell survival and proliferation, wich turns Oct2 into an attractive therapeutic target for non Hodking lymphoma patients. This critical Oct2 DLBCL cells dependency, is an example of “non oncogene addiction” that we recently defined based on our RNA interference screening. Oct-2 controls a network of regulatory relationships that sustain both normal GC B cells and malignant counterparts. In summary, we showed that Oct2 and OCA-B lie upstream of BCL6, one of the critical regulators of germinal center B cell differentiation. This suggests that Oct2-directed therapy should kill the same DLBCLs as BCL6-directed therapy. Furthermore, all GC and Post-GC B cells that were tested requiere Oct-2 for survival, indicating that Oct2-directed therapy might have a broder activity spectrum than the BCL6-directed therapy. The Oct2/OCA-B binding interface would be amenable to attack with potential manageable toxicity, since this interaction is exclusively required in GC B cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Down-regulation of BLIMP1α by the EBV oncogene, LMP-1, disrupts the plasma cell differentiation program and prevents viral replication in B cells: implications for the pathogenesis of EBV-associated B-cell lymphomas

Blood ◽  
2011 ◽  
Vol 117 (22) ◽  
pp. 5907-5917 ◽  
Author(s):  
Katerina Vrzalikova ◽  
Martina Vockerodt ◽  
Sarah Leonard ◽  
Andrew Bell ◽  
Wenbin Wei ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Virus Replication ◽  
Plasma Cell ◽  
Germinal Center ◽  
Lytic Cycle ◽  
Transformed Cells ◽  
Down Regulation ◽  
Plasma Cell Differentiation

AbstractAn important pathogenic event in Epstein-Barr virus (EBV)-associated lymphomas is the suppression of virus replication, which would otherwise lead to cell death. Because virus replication in B cells is intimately linked to their differentiation toward plasma cells, we asked whether the physiologic signals that drive normal B-cell differentiation are absent in EBV-transformed cells. We focused on BLIMP1α, a transcription factor that is required for plasma cell differentiation and that is inactivated in diffuse large B-cell lymphomas. We show that BLIMP1α expression is down-regulated after EBV infection of primary germinal center B cells and that the EBV oncogene, latent membrane protein-1 (LMP-1), is alone capable of inducing this down-regulation in these cells. Furthermore, the down-regulation of BLIMP1α by LMP-1 was accompanied by a partial disruption of the BLIMP1α transcriptional program, including the aberrant induction of MYC, the repression of which is required for terminal differentiation. Finally, we show that the ectopic expression of BLIMP1α in EBV-transformed cells can induce the viral lytic cycle. Our results suggest that LMP-1 expression in progenitor germinal center B cells could contribute to the pathogenesis of EBV-associated lymphomas by down-regulating BLIMP1α, in turn preventing plasma cell differentiation and induction of the viral lytic cycle.

scholarly journals Germinal center B cell development has distinctly regulated stages completed by disengagement from T cell help

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Ting-ting Zhang ◽  
David G Gonzalez ◽  
Christine M Cote ◽  
Steven M Kerfoot ◽  
Shaoli Deng ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
B Cell Differentiation ◽  
B Cell Maturation ◽  
Germinal Center B Cell ◽  
T Cell Help ◽  
Dose Dependent

To reconcile conflicting reports on the role of CD40 signaling in germinal center (GC) formation, we examined the earliest stages of murine GC B cell differentiation. Peri-follicular GC precursors first expressed intermediate levels of BCL6 while co-expressing the transcription factors RelB and IRF4, the latter known to repress Bcl6 transcription. Transition of GC precursors to the BCL6hi follicular state was associated with cell division, although the number of required cell divisions was immunogen dose dependent. Potentiating T cell help or CD40 signaling in these GC precursors actively repressed GC B cell maturation and diverted their fate towards plasmablast differentiation, whereas depletion of CD4+ T cells promoted this initial transition. Thus while CD40 signaling in B cells is necessary to generate the immediate precursors of GC B cells, transition to the BCL6hi follicular state is promoted by a regional and transient diminution of T cell help.

scholarly journals Cooperative transcriptional repression by BCL6 and BACH2 in germinal center B-cell differentiation

Blood ◽  
2014 ◽  
Vol 123 (7) ◽  
pp. 1012-1020 ◽  
Author(s):  
Chuanxin Huang ◽  
Huimin Geng ◽  
Isaac Boss ◽  
Ling Wang ◽  
Ari Melnick
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
Germinal Center ◽  
Transcriptional Repression ◽  
B Cell Development ◽  
B Cell Differentiation ◽  
Cooperative Action ◽  
Germinal Center B Cell ◽  
Key Points ◽  
Biochemical Mechanisms

Key Points BCL6 and BACH2 cooperatively regulate GC B-cell development. The cooperative action of BCL6 and BACH2 is through both transcriptional and biochemical mechanisms.

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