scholarly journals Human pre-B cells differentiate into Ig-secreting plasma cells in the presence of interleukin-4 and activated CD4+ T cells or their membranes

Blood ◽  
1993 ◽  
Vol 82 (9) ◽  
pp. 2781-2789
Author(s):  
J Punnonen ◽  
G Aversa ◽  
JE de Vries
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Cultures ◽  
Cd4 T Cells ◽  
Plasma Cells ◽  
Interleukin 4 ◽  
B Cell Differentiation ◽  
Ig Synthesis

Studies on human B-cell development have been hampered by the lack of reproducible culture techniques to induce pre-B cells to differentiate into Ig-secreting plasma cells. Here, we describe that highly purified surface (s) mu-, cytoplasmic (c) mu+, CD10+, CD19+ human pre-B cells derived from fetal bone marrow (BM) differentiate with high frequencies into Ig-secreting plasma cells, when cocultured with activated, cloned CD4+ T cells and with interleukin-4 (IL-4). Production of IgM, total IgG, IgG4, and IgE in pre-B-cell cultures was detected, indicating that the cells also underwent Ig isotype switching. Pre-B-cell differentiation occurred in the absence of BM stromal cells, IL-7, and stem cell factor (SCF). However, IL-7 significantly enhanced the levels of Ig produced, whereas SCF was ineffective. Neutralizing anti-IL-4 monoclonal antibodies (MoAbs) completely inhibited pre-B-cell differentiation showing the specificity of the reaction. Intact CD4+ T- cell clones could be replaced by membrane preparations of these cells, indicating that the costimulatory signals provided by the activated CD4+ T cells are contact-mediated. In contrast, anti-CD40 MoAbs failed to provide the costimulatory signal required for pre-B-cell differentiation, which may be related to the very low expression of CD40 on fetal BM B cells. Activated CD4+ T cells and IL-4 also induced s mu expression and Ig synthesis in cultures initiated with pre-B cells that had been preincubated in medium for 2 days, and from which spontaneously emerging s mu+ B cells were removed by using a fluorescence-activated cell sorter. These results support the notion that the Ig synthesis observed in pre-B-cell cultures was not caused by outgrowth and differentiation of cells that spontaneously matured into s mu+ B cells. In addition, IL-4 and CD4+ T cells strongly enhanced CD40 and HLA-DR expression on the majority of cultured pre-B cells, further indicating that CD4+ T cells and IL-4 activate bona fide pre-B cells. Taken together, these data indicate that activated CD4+ T cells and IL-4 can provide all the necessary signals required for human pre-B cells to differentiate into Ig-secreting plasma cells.

scholarly journals Human pre-B cells differentiate into Ig-secreting plasma cells in the presence of interleukin-4 and activated CD4+ T cells or their membranes

Blood ◽  
1993 ◽  
Vol 82 (9) ◽  
pp. 2781-2789 ◽  
Author(s):  
J Punnonen ◽  
G Aversa ◽  
JE de Vries
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Cultures ◽  
Cd4 T Cells ◽  
Plasma Cells ◽  
Interleukin 4 ◽  
B Cell Differentiation ◽  
Ig Synthesis

Abstract Studies on human B-cell development have been hampered by the lack of reproducible culture techniques to induce pre-B cells to differentiate into Ig-secreting plasma cells. Here, we describe that highly purified surface (s) mu-, cytoplasmic (c) mu+, CD10+, CD19+ human pre-B cells derived from fetal bone marrow (BM) differentiate with high frequencies into Ig-secreting plasma cells, when cocultured with activated, cloned CD4+ T cells and with interleukin-4 (IL-4). Production of IgM, total IgG, IgG4, and IgE in pre-B-cell cultures was detected, indicating that the cells also underwent Ig isotype switching. Pre-B-cell differentiation occurred in the absence of BM stromal cells, IL-7, and stem cell factor (SCF). However, IL-7 significantly enhanced the levels of Ig produced, whereas SCF was ineffective. Neutralizing anti-IL-4 monoclonal antibodies (MoAbs) completely inhibited pre-B-cell differentiation showing the specificity of the reaction. Intact CD4+ T- cell clones could be replaced by membrane preparations of these cells, indicating that the costimulatory signals provided by the activated CD4+ T cells are contact-mediated. In contrast, anti-CD40 MoAbs failed to provide the costimulatory signal required for pre-B-cell differentiation, which may be related to the very low expression of CD40 on fetal BM B cells. Activated CD4+ T cells and IL-4 also induced s mu expression and Ig synthesis in cultures initiated with pre-B cells that had been preincubated in medium for 2 days, and from which spontaneously emerging s mu+ B cells were removed by using a fluorescence-activated cell sorter. These results support the notion that the Ig synthesis observed in pre-B-cell cultures was not caused by outgrowth and differentiation of cells that spontaneously matured into s mu+ B cells. In addition, IL-4 and CD4+ T cells strongly enhanced CD40 and HLA-DR expression on the majority of cultured pre-B cells, further indicating that CD4+ T cells and IL-4 activate bona fide pre-B cells. Taken together, these data indicate that activated CD4+ T cells and IL-4 can provide all the necessary signals required for human pre-B cells to differentiate into Ig-secreting plasma cells.

Mutual Activation and Expansion of Donor CD4 + T Cells and B Cells in Transplants Play a Critical Role in the Initiation of Chronic Graft-Versus-Host Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1342-1342
Author(s):  
James Sundblom Young ◽  
Dongchang Zhao ◽  
Tangsheng Yi ◽  
Hongjun Liu ◽  
Defu Zeng
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Graft Versus Host Disease ◽  
Cd4 T Cells ◽  
Chronic Gvhd ◽  
B Cell Differentiation ◽  
T And B Cells ◽  
Graft Versus Host

Abstract Abstract 1342 Poster Board I-364 Chronic graft versus host disease (GVHD) is an autoimmune-like disease, in which both donor CD4+ T and B cells play important roles in the pathogenesis. However, it is unclear how donor CD4+ T and B cells interact in the context of chronic GVHD. In our current studies, we found that, in a new chronic GVHD model of MHC-matched DBA/2 donor to BALB/c host, depletion of donor CD4+ T cells in transplants prevented donor B220+ B cell upregulation of co-stimulatory molecules (i.e. B7.1, B7.2, and MHC II), prevented donor B cell differentiation into syndecan+ IgG anti-dsDNA autoantibody-producing plasma cells, and prevented the induction of chronic GVHD. In addition, we found that donor CD4+ T cells were able to drive both marginal zone B (AA4.1−B220+CD1dhiCD23lo) and follicular B (AA4.1−B220+CD23hiCD1dlo) cells to become IgG autoantibody-producing cells. On the other hand, depletion of donor B220+ B cells in transplants prevented expansion of donor-type CD4+ T cells that proliferated in response to donor DC stimulation, prevented the skewing of TCR CDR3-length of the donor CD4+ T cells as revealed by TCR spectratyping, and prevented induction of chronic GVHD. These results indicate that donor CD4+ T and B cells mutually activate each other in the chronic GVHD recipients; alloreactive donor CD4+ T cells activate and drive donor B cell differentiation into IgG autoantibody producing cells, in turn, donor B cells mediate the expansion and TCR-spreading of autoreactive donor CD4+ T cells. Therefore, donor CD4+ T and B cells in transplants orchestrate the development of chronic GVHD. This work is supported by NIH R01 AI066008. Disclosures No relevant conflicts of interest to declare.

scholarly journals Humoral helper activity for B-cell differentiation released from non- Hodgkin's lymphoma cells having both SRBC and complement receptors in the pokeweed mitogen system

Blood ◽  
1981 ◽  
Vol 57 (6) ◽  
pp. 1074-1080
Author(s):  
N Moriya ◽  
T Miyawaki ◽  
Y Ueno ◽  
S Koizumi ◽  
N Taniguchi
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Lymphoid Cells ◽  
Pokeweed Mitogen ◽  
Complement Receptors ◽  
B Cell Differentiation ◽  
Cell Leukemia

Abstract The majority of lymphoid cells from a patient with non-Hodgkin's lymphoma with leukemic transformation were demonstrated to carry receptors for both sheep erythrocytes and complements by the combined rosette assay using neuraminidase-treated sheep erythrocytes and complement-coated zymosan beads. Most of them were considered morphologically lymphoblasts and were positive for acid phosphatase staining. Terminal deoxynucleotidyl transferase activity was not detected in these cells. Lymphoid cells from this patient did not respond to the stimulation with phytohemagglutinin-P, concanavalin-A, and pokeweed mitogen (PWM). When these cells were cultured with PWM for 7 days, no plasma cell was generated. Although only a few plasma cells were generated in the PWM-stimulated culture of normal purified B cells alone, the addition of the patient's cells to purified normal B cells resulted in a markedly enhanced generation of plasma cells in response to PWM, as was the case with normal T cells. But leukemic cells either from a patient with T-cell leukemia not having complement receptors or from a patient with null-cell leukemia showed no enhancing ability in B- cell differentiation. In addition, the culture supernates of the patient's cells obtained after 24-hr PWM stimulation had an ability to promote B-cell differentiation comparable in activity to those from the PWM-stimulated normal T cells.

scholarly journals Humoral helper activity for B-cell differentiation released from non- Hodgkin's lymphoma cells having both SRBC and complement receptors in the pokeweed mitogen system

Blood ◽  
1981 ◽  
Vol 57 (6) ◽  
pp. 1074-1080 ◽  
Author(s):  
N Moriya ◽  
T Miyawaki ◽  
Y Ueno ◽  
S Koizumi ◽  
N Taniguchi
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Lymphoid Cells ◽  
Pokeweed Mitogen ◽  
Complement Receptors ◽  
B Cell Differentiation ◽  
Cell Leukemia

The majority of lymphoid cells from a patient with non-Hodgkin's lymphoma with leukemic transformation were demonstrated to carry receptors for both sheep erythrocytes and complements by the combined rosette assay using neuraminidase-treated sheep erythrocytes and complement-coated zymosan beads. Most of them were considered morphologically lymphoblasts and were positive for acid phosphatase staining. Terminal deoxynucleotidyl transferase activity was not detected in these cells. Lymphoid cells from this patient did not respond to the stimulation with phytohemagglutinin-P, concanavalin-A, and pokeweed mitogen (PWM). When these cells were cultured with PWM for 7 days, no plasma cell was generated. Although only a few plasma cells were generated in the PWM-stimulated culture of normal purified B cells alone, the addition of the patient's cells to purified normal B cells resulted in a markedly enhanced generation of plasma cells in response to PWM, as was the case with normal T cells. But leukemic cells either from a patient with T-cell leukemia not having complement receptors or from a patient with null-cell leukemia showed no enhancing ability in B- cell differentiation. In addition, the culture supernates of the patient's cells obtained after 24-hr PWM stimulation had an ability to promote B-cell differentiation comparable in activity to those from the PWM-stimulated normal T cells.

scholarly journals Optimized Protocols for in Vitro T Cell-Dependent and T Cell-Independent Activation for B Cell Differentiation Studies Using Limited Cells

2021 ◽  
Author(s):  
Casper Marsman ◽  
Dorit Verhoeven
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Formation ◽  
B Cell Differentiation ◽  
Differentiation Potential ◽  
Human B Cell

Background/methods: For mechanistic studies, in vitro human B cell differentiation and generation of plasma cells are invaluable techniques. However, the heterogeneity of both T cell-dependent (TD) and T cell-independent (TI) stimuli and the disparity of culture conditions used in existing protocols makes interpretation of results challenging. The aim of the present study was to achieve the most optimal B cell differentiation conditions using isolated CD19+ B cells and PBMC cultures. We addressed multiple seeding densities, different durations of culturing and various combinations of TD stimuli and TI stimuli including B cell receptor (BCR) triggering. B cell expansion, proliferation and differentiation was analyzed after 6 and 9 days by measuring B cell proliferation and expansion, plasmablast and plasma cell formation and immunoglobulin (Ig) secretion. In addition, these conditions were extrapolated using cryopreserved cells and differentiation potential was compared. Results: This study demonstrates improved differentiation efficiency after 9 days of culturing for both B cell and PBMC cultures using CD40L and IL-21 as TD stimuli and 6 days for CpG and IL-2 as TI stimuli. We arrived at optimized protocols requiring 2500 and 25.000 B cells per culture well for TD and TI assays, respectively. The results of the PBMC cultures were highly comparable to the B cell cultures, which allows dismissal of additional B cell isolation steps prior to culturing. In these optimized TD conditions, the addition of anti-BCR showed little effect on phenotypic B cell differentiation, however it interferes with Ig secretion measurements. Addition of IL-4 to the TD stimuli showed significantly lower Ig secretion. The addition of BAFF to optimized TI conditions showed enhanced B cell differentiation and Ig secretion in B cell but not in PBMC cultures. With this approach, efficient B cell differentiation and Ig secretion was accomplished when starting from fresh or cryopreserved samples. Conclusion: Our methodology demonstrates optimized TD and TI stimulation protocols for more indepth analysis of B cell differentiation in primary human B cell and PBMC cultures while requiring low amounts of B cells, making them ideally suited for future clinical and research studies on B cell differentiation of patient samples from different cohorts of B cell-mediated diseases.

scholarly journals Modulation of spontaneous B-cell differentiation in macroglobulinemia by retinoic acid

Blood ◽  
1994 ◽  
Vol 83 (8) ◽  
pp. 2206-2210 ◽  
Author(s):  
Y Levy ◽  
S Labaume ◽  
MC Gendron ◽  
JC Brouet
Keyword(s):  
Retinoic Acid ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
B Cell Differentiation ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Culture Supernatants

Abstract We previously showed that clonal blood B cells from patients with macroglobulinemia spontaneously differentiate in vitro to plasma cells. This process is dependent on an interleukin (IL)-6 autocrine pathway. We investigate here whether all-trans-retinoic acid (RA) interferes with B-cell differentiation either in patients with IgM gammapathy of undetermined significance (MGUS) or Waldenstrom's macroglobulinemia (WM). RA at a concentration of 10(-5) to 10(-8) mol/L inhibited by 50% to 80% the in vitro differentiation of purified B cells from four of five patients with MGUS and from one of five patients with WM as assessed by the IgM content of day 7 culture supernatants. We next determined whether this effect could be related to an inhibition of IL- 6 secretion by cultured B cells and/or a downregulation of the IL-6 receptor (IL-6R), which was constitutively expressed on patients' blood B cells. A 50% to 100% (mean, 80%) inhibition of IL-6 production was found in seven of 10 patients (five with MGUS and two with WM). The IL- 6R was no more detectable on cells from patients with MGUS after 2 days of treatment with RA and slightly downregulated in patients with WM. It was of interest that B cells susceptible to the action of RA belonged mostly to patients with IgM MGUS, which reinforces our previous data showing distinct requirements for IL-6-dependent differentiation of blood B cells from patients with VM or IgM MGUS.

scholarly journals Identification of a B cell differentiation factor(s) spontaneously produced by proliferating T cells in murine lupus strains of the lpr/lpr genotype.

1983 ◽  
Vol 157 (2) ◽  
pp. 730-742 ◽  
Author(s):  
G J Prud'Homme ◽  
C L Park ◽  
T M Fieser ◽  
R Kofler ◽  
F J Dixon ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Mouse Strain ◽  
Interleukin 2 ◽  
Lymphoid Cells ◽  
B Cell Differentiation ◽  
Differentiation Factor ◽  
Cell Differentiation Factor

Lymph node and spleen cells of the autoimmune MRL/Mp-lpr/lpr mouse strain spontaneously produce (in the absence of mitogenic stimulation) a factor(s) that induces B cell differentiation. This factor is not produced by the congenic MRL/n mouse strain that lacks the lpr gene or by normal mouse strains. However, lymphoid cells of the B6-lpr/lpr (B6/1) strain also produce a B cell differentiation factor. Although the factor acts on resting B cells, its effect is greatly magnified by activating the B cells with anti-mu or lipopolysaccharide. MRL/l mice begin producing the factor as early as 1 mo of age but levels increase with age and appearance of lymphoproliferation. Cell depletion studies reveal that this factor is produced by T cells of the Lyt-1+2-phenotype. Because of its association with the lpr/lpr genotype, we term this B cell differentiation factor L-BCDF. Functional analysis of L-BCDF reveals that it acts regardless of cell density in culture and in the absence of interleukin 2 (IL-2). In fact, the increase in the production of L-BCDF by MRL/1 T cells with aging occurs concomitantly with a marked decrease in their ability to produce IL-2. No T cell replacing factor activity or B cell growth factor-like activity can be detected in MRL/l-derived supernatants. L-BCDF induces both IgM and IgG synthesis in lipopolysaccharide-activated B cells; however, it has a greater effect on IgG secretion. In particular, the production of IgG1, IgG2a, and IgG2b are markedly enhanced in the presence of L-BCDF. The spontaneous production of L-BCDF by T cells of SLE mice of lpr/lpr genotype suggests an association of this factor with autoimmunity.

scholarly journals Viral Superantigen Drives Extrafollicular and Follicular B Cell Differentiation Leading to Virus-specific Antibody Production

1997 ◽  
Vol 185 (3) ◽  
pp. 551-562 ◽  
Author(s):  
Sanjiv A. Luther ◽  
Adam Gulbranson-Judge ◽  
Hans Acha-Orbea ◽  
Ian C.M. MacLennan
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Antibody Production ◽  
Specific Antibody ◽  
Germinal Centers ◽  
B Cell Differentiation ◽  
Virus Specific Antibody ◽  
Specific Antibody Production

Mouse mammary tumor virus (MMTV[SW]) encodes a superantigen expressed by infected B cells. It evokes an antibody response specific for viral envelope protein, indicating selective activation of antigen-specific B cells. The response to MMTV(SW) in draining lymph nodes was compared with the response to haptenated chicken gamma globulin (NP-CGG) using flow cytometry and immunohistology. T cell priming occurs in both responses, with T cells proliferating in association with interdigitating dendritic cells in the T zone. T cell proliferation continues in the presence of B cells in the outer T zone, and B blasts then undergo exponential growth and differentiation into plasma cells in the medullary cords. Germinal centers develop in both responses, but those induced by MMTV(SW) appear later and are smaller. Most T cells activated in the T zone and germinal centers in the MMTV(SW) response are superantigen specific and these persist for weeks in lymph nodes draining the site MMTV(SW) injection; this contrasts with the selective loss of superantigen-specific T cells from other secondary lymphoid tissues. The results indicate that this viral superantigen, when expressed by professional antigen-presenting cells, drives extrafollicular and follicular B cell differentiation leading to virus-specific antibody production.

Malignant B Cells Skew the Balance between Treg Cell and TH17 Cell Differentiation in B-Cell Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1347-1347
Author(s):  
Zhi-Zhang Yang ◽  
Anne J. Novak ◽  
Thomas E. Witzig ◽  
Stephen M. Ansell
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Th17 Cell Differentiation

Abstract Numerous clinical therapies have attempted to modulate tumor cell immunity, but for the most part, have proven unsuccessful. The inability to produce or augment an effective immune response is due in part to regulatory T (Treg) cells, which inhibit CD4 and CD8 T cell function. Our group has recently shown that Treg cell numbers are elevated in NHL tumors and that NHL B cells induce the development of Treg cells thereby inhibiting anti-tumor responses. The ability of NHL B cells to direct the cellular composition of their microenvironment is critical to our understanding of tumor immunity and we therefore wanted to determine if NHL B cells also directed the expansion or reduction of other T cell populations. IL-17-secreting CD4+ T cells (TH17), a newly characterized CD4+ T helper cell lineage, promote inflammation and play an important role in autoimmune disease. IL-17 has been shown to inhibit tumor cell growth suggesting a potential role for TH17 cells in anti-tumor immunity. We therefore set out to determine if TH17 cells were present in NHL tumors and whether or not their numbers were regulated by NHL B cells. Using unsorted mononuclear cells from malignant lymph nodes, we were unable to detect IL-17 expression in resting CD4+ T cells or CD4+ T cells activated with PMA/Ionomycin stimulation (less than 1%). However, IL-17-secreting CD4+ T cells could be detected in significant numbers in inflammatory tonsil and normal PBMCs. Interestingly, depletion of CD19+ NHL B cells from mononuclear cells obtained from patient biopsies resulted in detection of a clear population of IL-17-secreting CD4+ T cells (5%). These results suggest that NHL B cells suppress TH17 cell differentiation. The frequency of IL-17-secreting CD4+ T cells could not be further enhanced by the addition of exogenous TGF-b and IL-6, a cytokine combination favoring for TH17 differentiation, suggesting a further impairment of TH17 cell differentiation in the tumor microenvironment. In contrast, Foxp3 expression could be detected in resting CD4+ T cells (30%) and could be induced in CD4+CD25−Foxp3− T cells activated with TCR stimulation (28%). Contrary to the inhibition of TGF-b-mediated TH17 differentiation, Foxp3 expression could be dramatically upregulated by TGF-b in intratumoral CD4+ T cells (35%). In addition, lymphoma B cells strongly enhanced Foxp3 expression in intratumoral CD4+CD25−Foxp3−. Furthermore, when added together, the frequency of Foxp3+ T cells and Foxp3-inducible cells reached up to 60% of CD4+ T cells in tumor microenvironment of B-cell NHL. These findings suggest that the balance of effector TH17 cells and inhibitory Treg cells is disrupted in B-cell NHL and significantly favors the development of inhibitory Treg cells. Our data indicate that lymphoma B cells are key factor in regulating differentiation of intratumoral CD4+ T cells toward inhibitory CD4+ T cells.

scholarly journals The BTB-ZF transcription factor Zbtb20 is driven by Irf4 to promote plasma cell differentiation and longevity

2014 ◽  
Vol 211 (5) ◽  
pp. 827-840 ◽  
Author(s):  
Stéphane Chevrier ◽  
Dianne Emslie ◽  
Wei Shi ◽  
Tobias Kratina ◽  
Cameron Wellard ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Cell Cycle Progression ◽  
Plasma Cells ◽  
Cell Lineage ◽  
B Cell Differentiation ◽  
Antibody Secreting Cell ◽  
Important Player

The transcriptional network regulating antibody-secreting cell (ASC) differentiation has been extensively studied, but our current understanding is limited. The mechanisms of action of known “master” regulators are still unclear, while the participation of new factors is being revealed. Here, we identify Zbtb20, a Bcl6 homologue, as a novel regulator of late B cell development. Within the B cell lineage, Zbtb20 is specifically expressed in B1 and germinal center B cells and peaks in long-lived bone marrow (BM) ASCs. Unlike Bcl6, an inhibitor of ASC differentiation, ectopic Zbtb20 expression in primary B cells facilitates terminal B cell differentiation to ASCs. In plasma cell lines, Zbtb20 induces cell survival and blocks cell cycle progression. Immunized Zbtb20-deficient mice exhibit curtailed humoral responses and accelerated loss of antigen-specific plasma cells, specifically from the BM pool. Strikingly, Zbtb20 induction does not require Blimp1 but depends directly on Irf4, acting at a newly identified Zbtb20 promoter in ASCs. These results identify Zbtb20 as an important player in late B cell differentiation and provide new insights into this complex process.

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