Addendum: IgE+ memory B cells and plasma cells generated through a germinal-center pathway

T-dependent humoral responses generate long-lived memory B cells and plasma cells (PCs) predominantly through germinal center (GC) reaction. In human and mouse, memory B cells and long-lived PCs are also generated during immune responses to T-independent antigen, including bacterial polysaccharides, although the underlying mechanism for such T-independent humoral memory is not clear. While T-independent antigen can induce GCs, they are transient and thought to be nonproductive. Unexpectedly, by genetic fate-mapping, we find that these GCs actually output memory B cells and PCs. Using a conditional BCL6 deletion approach, we show memory B cells and PCs fail to last when T-independent GCs are precluded, suggesting that the GC experience per se is important for programming longevity of T-independent memory B cells and PCs. Consistent with the fact that infants cannot mount long-lived humoral memory to T-independent antigen, B cells from young animals intrinsically fail to form T-independent GCs. Our results suggest that T-independent GCs support humoral memory, and GC induction may be key to effective vaccines with T-independent antigen.

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The Normal Counterpart of IgD Myeloma Cells in Germinal Center Displays Extensively Mutated IgVH Gene, Cμ–Cδ Switch, and λ Light Chain Expression

Journal of Experimental Medicine ◽

10.1084/jem.187.8.1169 ◽

1998 ◽

Vol 187 (8) ◽

pp. 1169-1178 ◽

Cited By ~ 97

Author(s):

Christophe Arpin ◽

Odette de Bouteiller ◽

Diane Razanajaona ◽

Isabelle Fugier-Vivier ◽

Francine Brière ◽

...

Keyword(s):

Bone Marrow ◽

B Cells ◽

Light Chain ◽

Germinal Center ◽

Plasma Cells ◽

Precursor Cells ◽

Memory B Cells ◽

Hematopoietic Stem ◽

Myeloma Cells ◽

Λ Light Chain

Human myeloma are incurable hematologic cancers of immunoglobulin-secreting plasma cells in bone marrow. Although malignant plasma cells can be almost eradicated from the patient's bone marrow by chemotherapy, drug-resistant myeloma precursor cells persist in an apparently cryptic compartment. Controversy exists as to whether myeloma precursor cells are hematopoietic stem cells, pre–B cells, germinal center (GC) B cells, circulating memory cells, or plasma blasts. This situation reflects what has been a general problem in cancer research for years: how to compare a tumor with its normal counterpart. Although several studies have demonstrated somatically mutated immunoglobulin variable region genes in multiple myeloma, it is unclear if myeloma cells are derived from GCs or post-GC memory B cells. Immunoglobulin (Ig)D-secreting myeloma have two unique immunoglobulin features, including a biased λ light chain expression and a Cμ–Cδ isotype switch. Using surface markers, we have previously isolated a population of surface IgM−IgD+CD38+ GC B cells that carry the most impressive somatic mutation in their IgV genes. Here we show that this population of GC B cells displays the two molecular features of IgD-secreting myeloma cells: a biased λ light chain expression and a Cμ–Cδ isotype switch. The demonstration of these peculiar GC B cells to differentiate into IgD-secreting plasma cells but not memory B cells both in vivo and in vitro suggests that IgD-secreting plasma and myeloma cells are derived from GCs.

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Potential anti-EBV effects associated with elevated interleukin-21 levels: a case report

BMC Infectious Diseases ◽

10.1186/s12879-020-05609-z ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Kristian Assing ◽

Christian Nielsen ◽

Marianne Jakobsen ◽

Charlotte B. Andersen ◽

Kristin Skogstrand ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Plasma Cell ◽

Germinal Center ◽

Plasma Cells ◽

Cell Formation ◽

Memory B Cells ◽

Memory B Cell

Abstract Background Germinal center derived memory B cells and plasma cells constitute, in health and during EBV reactivation, the largest functional EBV reservoir. Hence, by reducing germinal center derived formation of memory B cells and plasma cells, EBV loads may be reduced. Animal and in-vitro models have shown that IL-21 can support memory B and plasma cell formation and thereby potentially contribute to EBV persistence. However, IL-21 also displays anti-viral effects, as mice models have shown that CD4+ T cell produced IL-21 is critical for the differentiation, function and survival of anti-viral CD8+ T cells able to contain chronic virus infections. Case presentation We present immunological work-up (flow-cytometry, ELISA and genetics) related to a patient suffering from a condition resembling B cell chronic active EBV infection, albeit with moderately elevated EBV copy numbers. No mutations in genes associated with EBV disease, common variable immunodeficiency or pertaining to the IL-21 signaling pathway (including hypermorphic IL-21 mutations) were found. Increased (> 5-fold increase 7 days post-vaccination) CD4+ T cell produced (p < 0.01) and extracellular IL-21 levels characterized our patient and coexisted with: CD8+ lymphopenia, B lymphopenia, hypogammaglobulinemia, compromised memory B cell differentiation, absent induction of B-cell lymphoma 6 protein (Bcl-6) dependent peripheral follicular helper T cells (pTFH, p = 0.01), reduced frequencies of peripheral CD4+ Bcl-6+ T cells (p = 0.05), compromised plasmablast differentiation (reduced protein vaccine responses (p < 0.001) as well as reduced Treg frequencies. Supporting IL-21 mediated suppression of pTFH formation, pTFH and CD4+ IL-21+ frequencies were strongly inversely correlated, prior to and after vaccination, in the patient and in controls, Spearman’s rho: − 0.86, p < 0.001. Conclusions To the best of our knowledge, this is the first report of elevated CD4+ IL-21+ T cell frequencies in human EBV disease. IL-21 overproduction may, apart from driving T cell mediated anti-EBV responses, disrupt germinal center derived memory B cell and plasma cell formation, and thereby contribute to EBV disease control.

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IgE+ memory B cells and plasma cells generated through a germinal-center pathway

Nature Immunology ◽

10.1038/ni.2256 ◽

2012 ◽

Vol 13 (4) ◽

pp. 396-404 ◽

Cited By ~ 103

Author(s):

Oezcan Talay ◽

Donghong Yan ◽

Hans D Brightbill ◽

Elizabeth E M Straney ◽

Meijuan Zhou ◽

...

Keyword(s):

B Cells ◽

Germinal Center ◽

Plasma Cells ◽

Memory B Cells

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Multiscale Modeling of Germinal Center Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells Differentiation as Regulated by Antigen Affinity-Based Tfh Cell Help

Frontiers in Immunology ◽

10.3389/fimmu.2020.620716 ◽

2021 ◽

Vol 11 ◽

Author(s):

Elena Merino Tejero ◽

Danial Lashgari ◽

Rodrigo García-Valiente ◽

Xuefeng Gao ◽

Fabien Crauste ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Fate ◽

Plasma Cell ◽

Germinal Center ◽

Plasma Cells ◽

Asymmetric Division ◽

Memory B Cells ◽

Memory B Cell ◽

Germinal Center Reaction

Germinal centers play a key role in the adaptive immune system since they are able to produce memory B cells and plasma cells that produce high affinity antibodies for an effective immune protection. The mechanisms underlying cell-fate decisions are not well understood but asymmetric division of antigen, B-cell receptor affinity, interactions between B-cells and T follicular helper cells (triggering CD40 signaling), and regulatory interactions of transcription factors have all been proposed to play a role. In addition, a temporal switch from memory B-cell to plasma cell differentiation during the germinal center reaction has been shown. To investigate if antigen affinity-based Tfh cell help recapitulates the temporal switch we implemented a multiscale model that integrates cellular interactions with a core gene regulatory network comprising BCL6, IRF4, and BLIMP1. Using this model we show that affinity-based CD40 signaling in combination with asymmetric division of B-cells result in switch from memory B-cell to plasma cell generation during the course of the germinal center reaction. We also show that cell fate division is unlikely to be (solely) based on asymmetric division of Ag but that BLIMP1 is a more important factor. Altogether, our model enables to test the influence of molecular modulations of the CD40 signaling pathway on the production of germinal center output cells.

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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

Frontiers in Immunology ◽

10.3389/fimmu.2021.716240 ◽

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.

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Early appearance of germinal center–derived memory B cells and plasma cells in blood after primary immunization

Journal of Experimental Medicine ◽

10.1084/jem.20042060 ◽

2005 ◽

Vol 201 (4) ◽

pp. 545-554 ◽

Cited By ~ 192

Author(s):

Elizabeth J. Blink ◽

Amanda Light ◽

Axel Kallies ◽

Stephen L. Nutt ◽

Philip D. Hodgkin ◽

...

Keyword(s):

B Cells ◽

Germinal Center ◽

Plasma Cells ◽

Affinity Maturation ◽

Memory B Cells ◽

Primary Immune Response ◽

Developmental Relationships ◽

Differentiation Potential ◽

Specific Memory ◽

Secondary Lymphoid Organs

Immunization with a T cell–dependent antigen elicits production of specific memory B cells and antibody-secreting cells (ASCs). The kinetic and developmental relationships between these populations and the phenotypic forms they and their precursors may take remain unclear. Therefore, we examined the early stages of a primary immune response, focusing on the appearance of antigen-specific B cells in blood. Within 1 wk, antigen-specific B cells appear in the blood with either a memory phenotype or as immunoglobulin (Ig)G1 ASCs expressing blimp-1. The memory cells have mutated VH genes; respond to the chemokine CXCL13 but not CXCL12, suggesting recirculation to secondary lymphoid organs; uniformly express B220; show limited differentiation potential unless stimulated by antigen; and develop independently of blimp-1 expression. The antigen-specific IgG1 ASCs in blood show affinity maturation paralleling that of bone marrow ASCs, raising the possibility that this compartment is established directly by blood-borne ASCs. We find no evidence for a blimp-1–expressing preplasma memory compartment, suggesting germinal center output is restricted to ASCs and B220+ memory B cells, and this is sufficient to account for the process of affinity maturation.

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Interleukin-24 inhibits the plasma cell differentiation program in human germinal center B cells

Blood ◽

10.1182/blood-2009-05-220251 ◽

2010 ◽

Vol 115 (9) ◽

pp. 1718-1726 ◽

Cited By ~ 29

Author(s):

Ghyath Maarof ◽

Laurence Bouchet-Delbos ◽

Hélène Gary-Gouy ◽

Ingrid Durand-Gasselin ◽

Roman Krzysiek ◽

...

Keyword(s):

Cell Differentiation ◽

B Cells ◽

B Cell ◽

Cell Fate ◽

Plasma Cell ◽

Germinal Center ◽

Molecular Mechanisms ◽

Plasma Cells ◽

Memory B Cells ◽

Plasma Cell Differentiation

Abstract Complex molecular mechanisms control B-cell fate to become a memory or a plasma cell. Interleukin-24 (IL-24) is a class II family cytokine of poorly understood immune function that regulates the cell cycle. We previously observed that IL-24 is strongly expressed in leukemic memory-type B cells. Here we show that IL-24 is also expressed in human follicular B cells; it is more abundant in CD27+ memory B cells and CD5-expressing B cells, whereas it is low to undetectable in centroblasts and plasma cells. Addition of IL-24 to B cells, cultured in conditions shown to promote plasma cell differentiation, strongly inhibited plasma cell generation and immunoglobulin G (IgG) production. By contrast, IL-24 siRNA increased terminal differentiation of B cells into plasma cells. IL-24 is optimally induced by BCR triggering and CD40 engagement; IL-24 increased CD40-induced B-cell proliferation and modulated the transcription of key factors involved in plasma cell differentiation. It also inhibited activation-induced tyrosine phosphorylation of signal transducer and activator of transcription-3 (STAT-3), and inhibited the transcription of IL-10. Taken together, our results indicate that IL-24 is a novel cytokine involved in T-dependent antigen (Ag)–driven B-cell differentiation and suggest its physiologic role in favoring germinal center B-cell maturation in memory B cells at the expense of plasma cells.

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The Development of Optimally Responsive Plasmodium-specific CD73+CD80+ IgM+ Memory B cells Requires Intrinsic BCL6 expression but not CD4+ Tfh cells

10.1101/564351 ◽

2019 ◽

Cited By ~ 3

Author(s):

Gretchen Harms Pritchard ◽

Akshay T. Krishnamurty ◽

Jason Netland ◽

E. Nicole Arroyo ◽

Kennidy K. Takehara ◽

...

Keyword(s):

B Cells ◽

Germinal Center ◽

Plasma Cells ◽

Germinal Centers ◽

Memory B Cells ◽

Effector Cells ◽

High Affinity ◽

Tfh Cells ◽

Follicular Helper ◽

Bcl6 Expression

SummaryHumoral immunity depends upon the development of long-lived, antibody-secreting plasma cells and rapidly responsive memory B cells (MBCs). The differentiation of high affinity, class-switched MBCs after immunization is critically dependent upon BCL6 expression in germinal center (GC) B cells and CD4+ T follicular helper (Tfh) cells. It is less well understood how more recently described MBC subsets are generated, including the CD73+CD80+ IgM+ MBCs that initially form antibody-secreting effector cells in response to a secondary Plasmodium infection. Herein, we interrogated how BCL6 expression in both B and CD4+ T cells influenced the formation of heterogeneous Plasmodium-specific MBC populations. All Plasmodium-specific CD73+CD80+ MBCs required BCL6 expression for their formation, suggesting germinal center dependence. Further dissection of the CD4+ T and B cell interactions however revealed that somatically hypermutated CD73+CD80+ IgM+ MBCs can form not only in the absence of germinal centers, but also in the absence of CXCR5+ CD4+ Tfh cells.

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“B” aware: Memory lane access is restricted!

Journal of Experimental Medicine ◽

10.1084/jem.20200568 ◽

2020 ◽

Vol 217 (7) ◽

Author(s):

Ruth Kennedy ◽

Ulf Klein

Keyword(s):

B Cells ◽

Adaptive Immunity ◽

Germinal Center ◽

Molecular Mechanisms ◽

Plasma Cells ◽

Transcriptional Repressor ◽

Memory B Cells ◽

High Affinity ◽

Repressor Complex

Understanding the molecular mechanisms that govern the differentiation of high-affinity germinal center (GC) B cells into memory B cells versus plasma cells is a major quest of adaptive immunity. In this issue, Toboso-Navasa et al. (https://doi.org/10.1084/jem.20191933) provide evidence that the MYC–MIZ1 transcriptional repressor complex restricts the differentiation of GC B cells into MBCs.

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