scholarly journals Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells

2020 ◽  
Vol 218 (4) ◽  
Author(s):  
Juhee Pae ◽  
Jonatan Ersching ◽  
Tiago B.R. Castro ◽  
Marta Schips ◽  
Luka Mesin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Clonal Expansion ◽  
Affinity Maturation ◽  
Cyclin D3 ◽  
Dark Zone ◽  
Follicular Helper ◽  
Cell Cycle Regulator Cyclin

During affinity maturation, germinal center (GC) B cells alternate between proliferation and somatic hypermutation in the dark zone (DZ) and affinity-dependent selection in the light zone (LZ). This anatomical segregation imposes that the vigorous proliferation that allows clonal expansion of positively selected GC B cells takes place ostensibly in the absence of the signals that triggered selection in the LZ, as if by “inertia.” We find that such inertial cycles specifically require the cell cycle regulator cyclin D3. Cyclin D3 dose-dependently controls the extent to which B cells proliferate in the DZ and is essential for effective clonal expansion of GC B cells in response to strong T follicular helper (Tfh) cell help. Introduction into the Ccnd3 gene of a Burkitt lymphoma–associated gain-of-function mutation (T283A) leads to larger GCs with increased DZ proliferation and, in older mice, clonal B cell lymphoproliferation, suggesting that the DZ inertial cell cycle program can be coopted by B cells undergoing malignant transformation.

scholarly journals Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells

2020 ◽  
Author(s):  
Juhee Pae ◽  
Jonatan Ersching ◽  
Tiago B. R. Castro ◽  
Marta Schips ◽  
Luka Mesin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Clonal Expansion ◽  
Affinity Maturation ◽  
Cyclin D3 ◽  
Dark Zone ◽  
Follicular Helper ◽  
Cell Cycle Regulator Cyclin

AbstractDuring affinity maturation, germinal center (GC) B cells alternate between proliferation and so-matic hypermutation in the dark zone (DZ) and affinity-dependent selection in the light zone (LZ). This anatomical segregation imposes that the vigorous proliferation that allows clonal expansion of positively-selected GC B cells takes place ostensibly in the absence of the signals that triggered selection in the LZ, as if by “inertia.” We find that such inertial cycles specifically require the cell cycle regulator cyclin D3. Cyclin D3 dose-dependently controls the extent to which B cells proliferate in the DZ and is essential for effective clonal expansion of GC B cells in response to strong T follicular helper (Tfh) cell help. Introduction into the Ccnd3 gene of a Burkitt lymphoma-associated gain-of-function mutation (T283A) leads to larger GCs with increased DZ proliferation and, in older mice, to clonal B cell lymphoproliferation, suggesting that the DZ inertial cell cycle program can be coopted by B cells undergoing malignant transformation.

scholarly journals Cyclin D3 Governs Clonal Expansion of Dark Zone Germinal Center B Cells

Cell Reports ◽  
2020 ◽  
Vol 33 (7) ◽  
pp. 108403
Author(s):  
Parham Ramezani-Rad ◽  
Cindi Chen ◽  
Zilu Zhu ◽  
Robert C. Rickert
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Clonal Expansion ◽  
Cyclin D3 ◽  
Dark Zone ◽  
Germinal Center B Cells

scholarly journals Cbl and Cbl-b control the germinal center reaction by facilitating naive B cell antigen processing

2020 ◽  
Vol 217 (9) ◽  
Author(s):  
Xin Li ◽  
Liying Gong ◽  
Alexandre P. Meli ◽  
Danielle Karo-Atar ◽  
Weili Sun ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Antigen Processing ◽  
Cell Interaction ◽  
Affinity Maturation ◽  
Antigen Uptake ◽  
Cell Antigen ◽  
Germinal Center Reaction ◽  
Follicular Helper

Antigen uptake and presentation by naive and germinal center (GC) B cells are different, with the former expressing even low-affinity BCRs efficiently capture and present sufficient antigen to T cells, whereas the latter do so more efficiently after acquiring high-affinity BCRs. We show here that antigen uptake and processing by naive but not GC B cells depend on Cbl and Cbl-b (Cbls), which consequently control naive B and cognate T follicular helper (Tfh) cell interaction and initiation of the GC reaction. Cbls mediate CD79A and CD79B ubiquitination, which is required for BCR-mediated antigen endocytosis and postendocytic sorting to lysosomes, respectively. Blockade of CD79A or CD79B ubiquitination or Cbls ligase activity is sufficient to impede BCR-mediated antigen processing and GC development. Thus, Cbls act at the entry checkpoint of the GC reaction by promoting naive B cell antigen presentation. This regulation may facilitate recruitment of naive B cells with a low-affinity BCR into GCs to initiate the process of affinity maturation.

scholarly journals WASp Is Crucial for the Unique Architecture of the Immunological Synapse in Germinal Center B-Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Yanan Li ◽  
Anshuman Bhanja ◽  
Arpita Upadhyaya ◽  
Xiaodong Zhao ◽  
Wenxia Song
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lipid Bilayers ◽  
Germinal Center ◽  
Actin Polymerization ◽  
Immunological Synapse ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
Membrane Protrusions ◽  
Germinal Center B Cells

B-cells undergo somatic hypermutation and affinity maturation in germinal centers. Somatic hypermutated germinal center B-cells (GCBs) compete to engage with and capture antigens on follicular dendritic cells. Recent studies show that when encountering membrane antigens, GCBs generate actin-rich pod-like structures with B-cell receptor (BCR) microclusters to facilitate affinity discrimination. While deficiencies in actin regulators, including the Wiskott-Aldrich syndrome protein (WASp), cause B-cell affinity maturation defects, the mechanism by which actin regulates BCR signaling in GBCs is not fully understood. Using WASp knockout (WKO) mice that express Lifeact-GFP and live-cell total internal reflection fluorescence imaging, this study examined the role of WASp-mediated branched actin polymerization in the GCB immunological synapse. After rapid spreading on antigen-coated planar lipid bilayers, GCBs formed microclusters of phosphorylated BCRs and proximal signaling molecules at the center and the outer edge of the contact zone. The centralized signaling clusters localized at actin-rich GCB membrane protrusions. WKO reduced the centralized micro-signaling clusters by decreasing the number and stability of F-actin foci supporting GCB membrane protrusions. The actin structures that support the spreading membrane also appeared less frequently and regularly in WKO than in WT GCBs, which led to reductions in both the level and rate of GCB spreading and antigen gathering. Our results reveal essential roles for WASp in the generation and maintenance of unique structures for GCB immunological synapses.

scholarly journals Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses

2018 ◽  
Vol 215 (6) ◽  
pp. 1571-1588 ◽  
Author(s):  
Norbert Pardi ◽  
Michael J. Hogan ◽  
Martin S. Naradikian ◽  
Kaela Parkhouse ◽  
Derek W. Cain ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Neutralizing Antibodies ◽  
Affinity Maturation ◽  
Modified Nucleosides ◽  
Vaccine Platform ◽  
Intradermal Vaccination ◽  
Cell Responses ◽  
Follicular Helper

T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4+ T cell responses and potent neutralizing antibody responses in mice and nonhuman primates. Importantly, the strong antigen-specific Tfh cell response and high numbers of GC B cells and plasma cells were associated with long-lived and high-affinity neutralizing antibodies and durable protection. Comparative studies demonstrated that nucleoside-modified mRNA-LNP vaccines outperformed adjuvanted protein and inactivated virus vaccines and pathogen infection. The incorporation of noninflammatory, modified nucleosides in the mRNA is required for the production of large amounts of antigen and for robust immune responses.

scholarly journals Human germinal center B cells express the apoptosis-inducing genes Fas, c-myc, P53, and Bax but not the survival gene bcl-2.

1996 ◽  
Vol 183 (3) ◽  
pp. 971-977 ◽  
Author(s):  
H Martinez-Valdez ◽  
C Guret ◽  
O de Bouteiller ◽  
I Fugier ◽  
J Banchereau ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Cell Subset ◽  
Variable Region ◽  
Negative Regulator ◽  
Memory B Cell ◽  
Survival Gene

During T cell-dependent antibody responses, B cells within germinal centers (GC) alter the affinity of their antigen receptor by introducing somatic mutations into variable region of immunoglobulin (IgV) genes. During this process, GC B cells are destined to die unless positively selected by antigens and CD40-ligand. To understand survival/death control of germinal center B cell, the expression of four apoptosis-inducing genes, Fas, c-myc, Bax, and P53, together with the survival gene bcl-2, has been analyzed herein among purified tonsillar naive, GC, and memory B cells. IgD+CD38- naive B cells were separated into CD23- (mature B cell [Bm]1) subset and CD23+ (Bm2), IgD-CD38+ GC B cells were separated into subsets of CD77+ centroblasts (Bm3) and CD77- centrocytes (Bm4), whereas IgD-CD38- cells represented the Bm5 memory B cell subset. Sequence analysis of IgV region genes indicated that somatic hypermutation was triggered in the Bm3 centroblast subset. Here we show that bcl-2 is only detectable with naive (Bm1 and 2) and memory B cell (Bm5) subsets, whereas all four apoptosis-inducing genes were most significantly expressed within GC B cells. Fas was equally expressed in Bm3 centroblasts and Bm4 centrocytes, whereas Bax was most significantly expressed in Bm4 centrocytes. c-myc, a positive regulator of cell cycle, was most significantly expressed in proliferating Bm3 centroblasts, whereas P53, a negative regulator of cell cycle, was most signficantly expressed in nonproliferating Bm4 centrocytes. The present results indicate that the survival/death of GC B cells are regulated by the up- and downregulation of multiple genes, among which the expression of c-myc and P53 in the absence of bcl-2 may prime the proliferating Bm3 centroblasts and nonproliferating Bm4 centrocytes to apoptosis.

Cyclin D3 Is Required for the Germinal Center Reaction

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2580-2580
Author(s):  
Jonathan U. Peled ◽  
J. Jessica Yu ◽  
Beibei Belinda Ding ◽  
Rita Shaknovich ◽  
Piotr Sicinski ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Affinity Maturation ◽  
Cyclin D3 ◽  
G1 Phase ◽  
Lymphoid Tissues ◽  
Cyclin D2

Abstract Germinal Centers (GC) of secondary lymphoid tissues are critical to mounting a high-affinity humoral immune response. B cells within the GC undergo rapid clonal expansion and selection while diversifying their antibody genes through class switch recombination and somatic hypermutation. Although it is generally believed that GC B cells employ a unique proliferative program to accommodate these processes, very little is known about how the GC-associated cell cycle is orchestrated. The D-type cyclins are important regulators of the G1 phase of the cell cycle and are the ultimate targets of many mitogenic and oncogenic stimuli. The Cyclin D3 gene is rearranged and over-expressed in certain mature B cell malignancies, and its overexpression has been reported to predict poor clinical outcome in patients with diffuse large B cell lymphoma. It has been observed that during their development, B cells switch from expressing cyclin D2 to cyclin D3 when they are recruited into the GC response. It is unclear, however, whether this switch simply reflects a change in the transcription factors that govern cyclin expression or serves a biological mandate. Here we report that mice deficient in cyclin D3 are profoundly impaired in their ability to form GCs as measured by immunohistochemistry and flow cytometry. Production of antigen-specific antibodies and affinity maturation, as ascertained by ELISA, are concomitantly reduced in these animals. These phenotypes can be at least partially explained by a significant block in the G1-phase of the cell cycle of GC B cells in vivo. Interestingly, this block in the G1-S transition is observed despite an apparent compensatory increase in cyclin D2 expression. In addition, naive B cells activated in vitro by either LPS or LPS and IL-4 display only minor changes in cell-cycle profile, suggesting that a specific requirement for cyclin D3 is unique to GC B cells. We also find moderately reduced Bcl6 mRNA expression in both naïve and GC B cells from the cyclin D3 knockout mice. Since Bcl6 is a master regulator of the GC response, decreased activity of this transcriptional repressor may further contribute to the severity of the GC phenotype. This is the first demonstration that cyclin D3 plays a unique role during the GC response in that it is required for its optimal structure and function. In addition to expanding appreciation for the cell type- and tissue-specific functions of the three D-type cyclin molecules, our findings have implications for understanding the role of Cyclin D3 in human B cell lymphomas.

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 CD4-deficient T helper cells are capable of supporting somatic hypermutation and affinity maturation of germinal center B cells

2002 ◽  
Vol 32 (11) ◽  
pp. 3315-3325 ◽  
Author(s):  
Biao Zheng ◽  
Zeynep Z. Ozen ◽  
Shutong Cao ◽  
Ye Zhang ◽  
Shuhua Han
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
T Helper Cells ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
T Helper ◽  
Helper Cells ◽  
Germinal Center B Cells
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