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

2019 ◽  
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.

scholarly journals Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells

2017 ◽  
Vol 214 (5) ◽  
pp. 1259-1267 ◽  
Author(s):  
Nike J. Kräutler ◽  
Dan Suan ◽  
Danyal Butt ◽  
Katherine Bourne ◽  
Jana R. Hermes ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Protective Immunity ◽  
Plasma Cells ◽  
Discrete Subset ◽  
Autoantibody Production ◽  
High Affinity ◽  
Tfh Cells ◽  
Follicular Helper

Plasma cells (PCs) derived from germinal centers (GCs) secrete the high-affinity antibodies required for long-term serological immunity. Nevertheless, the process whereby GC B cells differentiate into PCs is uncharacterized, and the mechanism underlying the selective PC differentiation of only high-affinity GC B cells remains unknown. In this study, we show that differentiation into PCs is induced among a discrete subset of high-affinity B cells residing within the light zone of the GC. Initiation of differentiation required signals delivered upon engagement with intact antigen. Signals delivered by T follicular helper cells were not required to initiate differentiation but were essential to complete the differentiation process and drive migration of maturing PCs through the dark zone and out of the GC. This bipartite or two-signal mechanism has likely evolved to both sustain protective immunity and avoid autoantibody production.

scholarly journals A distinct subpopulation of CD25− T-follicular regulatory cells localizes in the germinal centers

2017 ◽  
Vol 114 (31) ◽  
pp. E6400-E6409 ◽  
Author(s):  
James Badger Wing ◽  
Yohko Kitagawa ◽  
Michela Locci ◽  
Hannah Hume ◽  
Christopher Tay ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Germinal Center ◽  
Germinal Centers ◽  
Regulatory Cells ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Distinct Subpopulation ◽  
Wide Range ◽  
Multistep Process

T-follicular helper (Tfh) cells differentiate through a multistep process, culminating in germinal center (GC) localized GC-Tfh cells that provide support to GC-B cells. T-follicular regulatory (Tfr) cells have critical roles in the control of Tfh cells and GC formation. Although Tfh-cell differentiation is inhibited by IL-2, regulatory T (Treg) cell differentiation and survival depend on it. Here, we describe a CD25− subpopulation within both murine and human PD1+CXCR5+Foxp3+ Tfr cells. It is preferentially located in the GC and can be clearly differentiated from CD25+ non–GC-Tfr, Tfh, and effector Treg (eTreg) cells by the expression of a wide range of molecules. In comparison to CD25+ Tfr and eTreg cells, CD25− Tfr cells partially down-regulate IL-2–dependent canonical Treg features, but retain suppressive function, while simultaneously up-regulating genes associated with Tfh and GC-Tfh cells. We suggest that, similar to Tfh cells, Tfr cells follow a differentiation pathway generating a mature GC-localized subpopulation, CD25− Tfr cells.

scholarly journals Intrinsic properties of human germinal center B cells set antigen affinity thresholds

2018 ◽  
Vol 3 (29) ◽  
pp. eaau6598 ◽  
Author(s):  
Kihyuck Kwak ◽  
Nicolas Quizon ◽  
Haewon Sohn ◽  
Avva Saniee ◽  
Javier Manzella-Lapeira ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Synapse Formation ◽  
Plasma Cells ◽  
Affinity Maturation ◽  
Intrinsic Properties ◽  
High Affinity ◽  
Follicular Helper ◽  
Bcr Signaling ◽  
Engagement And Disengagement

Protective antibody responses to vaccination or infection depend on affinity maturation, a process by which high-affinity germinal center (GC) B cells are selected on the basis of their ability to bind, gather, and present antigen to T follicular helper (Tfh) cells. Here, we show that human GC B cells have intrinsically higher-affinity thresholds for both B cell antigen receptor (BCR) signaling and antigen gathering as compared with naïve B cells and that these functions are mediated by distinct cellular structures and pathways that ultimately lead to antigen affinity– and Tfh cell–dependent differentiation to plasma cells. GC B cells bound antigen through highly dynamic, actin- and ezrin-rich pod-like structures that concentrated BCRs. The behavior of these structures was dictated by the intrinsic antigen affinity thresholds of GC B cells. Low-affinity antigens triggered continuous engagement and disengagement of membrane-associated antigens, whereas high-affinity antigens induced stable synapse formation. The pod-like structures also mediated affinity-dependent antigen internalization by unconventional pathways distinct from those of naïve B cells. Thus, intrinsic properties of human GC B cells set thresholds for affinity selection.

scholarly journals Positive Selection in the Light Zone of Germinal Centers

2021 ◽  
Vol 12 ◽  
Author(s):  
Rinako Nakagawa ◽  
Dinis Pedro Calado
Keyword(s):  
B Cells ◽  
Positive Selection ◽  
B Cell ◽  
Plasma Cells ◽  
Selection Process ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
Memory B Cells ◽  
Cell Fates ◽  
High Affinity

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.

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.

scholarly journals bcl-2 Transgene Expression Inhibits Apoptosis in the Germinal Center and Reveals Differences in the Selection of Memory B Cells and Bone Marrow Antibody-Forming Cells

2000 ◽  
Vol 191 (3) ◽  
pp. 475-484 ◽  
Author(s):  
Kenneth G.C. Smith ◽  
Amanda Light ◽  
Lorraine A. O'Reilly ◽  
Soon-Meng Ang ◽  
Andreas Strasser ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Germinal Center ◽  
Low Frequency ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
Memory B Cells ◽  
High Affinity ◽  
Excessive Number ◽  
Selection Of

Immunization with T cell–dependent antigens generates long-lived memory B cells and antibody-forming cells (AFCs). Both populations originate in germinal centers and, predominantly, produce antibodies with high affinity for antigen. The means by which germinal center B cells are recruited into these populations remains unclear. We have examined affinity maturation of antigen-specific B cells in mice expressing the cell death inhibitor bcl-2 as a transgene. Such mice had reduced apoptosis in germinal centers and an excessive number of memory B cells with a low frequency of V gene somatic mutation, including those mutations encoding amino acid exchanges known to enhance affinity. Despite the frequency of AFCs being increased in bcl-2–transgenic mice, the fraction secreting high-affinity antibody in the bone marrow at day 42 remained unchanged compared with controls. The inability of BCL-2 to alter selection of bone marrow AFCs is consistent with these cells being selected within the germinal center on the basis of their affinity being above some threshold rather than their survival being due to a selective competition for an antigen-based signal. Continuous competition for antigen does, however, explain formation of the memory compartment.

scholarly journals “B” aware: Memory lane access is restricted!

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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