Activation sensitizes human memory B cells to B-cell receptor-induced apoptosis

AbstractSignaling via the B-cell receptor (BCR) is a key driver and therapeutic target in chronic lymphocytic leukemia (CLL). BCR stimulation of CLL cells induces expression of eIF4A, an initiation factor important for translation of multiple oncoproteins, and reduces expression of PDCD4, a natural inhibitor of eIF4A, suggesting that eIF4A may be a critical nexus controlling protein expression downstream of the BCR in these cells. We, therefore, investigated the effect of eIF4A inhibitors (eIF4Ai) on BCR-induced responses. We demonstrated that eIF4Ai (silvestrol and rocaglamide A) reduced anti-IgM-induced global mRNA translation in CLL cells and also inhibited accumulation of MYC and MCL1, key drivers of proliferation and survival, respectively, without effects on upstream signaling responses (ERK1/2 and AKT phosphorylation). Analysis of normal naïve and non-switched memory B cells, likely counterparts of the two main subsets of CLL, demonstrated that basal RNA translation was higher in memory B cells, but was similarly increased and susceptible to eIF4Ai-mediated inhibition in both. We probed the fate of MYC mRNA in eIF4Ai-treated CLL cells and found that eIF4Ai caused a profound accumulation of MYC mRNA in anti-IgM treated cells. This was mediated by MYC mRNA stabilization and was not observed for MCL1 mRNA. Following drug wash-out, MYC mRNA levels declined but without substantial MYC protein accumulation, indicating that stabilized MYC mRNA remained blocked from translation. In conclusion, BCR-induced regulation of eIF4A may be a critical signal-dependent nexus for therapeutic attack in CLL and other B-cell malignancies, especially those dependent on MYC and/or MCL1.

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Characterization of B-cell Receptor Heavy Chain Complementarity-determining Region 3 Repertoire Based on the Differences of Symbiotic Microorganisms in the Gut of Mice

10.21203/rs.3.rs-203289/v1 ◽

2021 ◽

Author(s):

Jun Li ◽

Yurong Pan ◽

Qingqing Ma ◽

Long Ma ◽

Bin Shi ◽

...

Keyword(s):

Small Intestine ◽

B Cells ◽

B Cell ◽

Heavy Chain ◽

Intestinal Microflora ◽

Cell Receptor ◽

Memory B Cells ◽

B Cell Receptor ◽

Positive Effects ◽

Significant Difference

Abstract Background Colonization of gut microorganism is related to maturation of B cells in peripheral immune organs. This study aims to investigate the effect of intestinal microflora in Germ-free (GF), Specific Pathogen-free (SPF) and Clean (CL) BALB/C mice to small intestine total B-cell and memory B-cell receptor (BCR) complementary-determining region 3 (CDR3) repertoire. Results The composition and characteristics of intestinal microflora were analyzed by 16S rDNA sequencing. Genomic DNA extracted from small intestine tissue and memory B-cells of GF, SPF and CL mice were conducted via high-throughput DNA sequencing methods. As expected, significant differences of gut microflora diversity were observed in the three mice groups. CL group showed the most diversity, followed by SPF group, and GF group had the lowest diversity. Moreover, anormogenesis of intestinal lymphoid tissue were observed in GF mice. Diversity of the BCR heavy chain CDR3 repertoire in memory B cells were significant difference among three groups, but not in total B cells. The nucleotide polymorphism, usage frequency of gene segments (V, D, J, V–J gene segments) and amino acid of total B cells and memory B cells CDR3 were comparable among three mice groups, and there was significant difference between CL and GF mice groups. Conclusions The results of this study advocate that the colonization of intestinal microorganisms affect the diversity of B cells CDR3 repertoire. Elucidating mechanism of microbiome participated in the function of intestinal mucosal immune system may have positive effects on human health, and it requires further investigation.

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A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells

Blood ◽

10.1182/blood-2002-11-3569 ◽

2003 ◽

Vol 101 (11) ◽

pp. 4500-4504 ◽

Cited By ~ 463

Author(s):

Nadia L. Bernasconi ◽

Nobuyuki Onai ◽

Antonio Lanzavecchia

Keyword(s):

B Cells ◽

B Cell ◽

Constitutive Expression ◽

Human Memory ◽

Cell Receptor ◽

Primary Response ◽

Memory B Cells ◽

Toll Like Receptors ◽

Polyclonal Activation ◽

B Cell Subsets

Abstract Toll-like receptors (TLRs) are pattern recognition receptors that trigger innate immunity. In this study we investigated the expression of 10 TLRs in human naive and memory B-cell subsets. We report that in human naive B cells most TLRs are expressed at low to undetectable levels, but the expression of TLR9 and TLR10 is rapidly induced following B-cell-receptor (BCR) triggering. In contrast, memory B cells express several TLRs at constitutively high levels. The differential expression of TLR9 correlates with responsiveness to its agonist, CpG DNA. Thus, human memory B cells proliferate and differentiate to immunoglobulin (Ig)–secreting cells in response to CpG, while naive B do so only if simultaneously triggered through the BCR. The BCR-induced expression of TLRs in human naive B cells prevents polyclonal activation in a primary response, because it restricts stimulation to antigen-specific B cells. In contrast, the constitutive expression of TLRs in memory B cells allows polyclonal activation of the entire memory pool. Thus, in human B cells TLRs are downstream of BCR and play a role both in the primary response and in the memory phase.

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Intrinsic Differences in the Initiation of B Cell Receptor Signaling Favor Responses of Human IgG+ Memory B Cells over IgM+ Naive B Cells

The Journal of Immunology ◽

10.4049/jimmunol.1102322 ◽

2012 ◽

Vol 188 (7) ◽

pp. 3332-3341 ◽

Cited By ~ 19

Author(s):

Angel M. Davey ◽

Susan K. Pierce

Keyword(s):

B Cells ◽

B Cell ◽

Cell Receptor ◽

Memory B Cells ◽

B Cell Receptor ◽

Receptor Signaling ◽

Human Igg ◽

B Cell Receptor Signaling ◽

Cell Receptor Signaling

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Decision letter: Malaria-associated atypical memory B cells exhibit markedly reduced B cell receptor signaling and effector function

10.7554/elife.07218.016 ◽

2015 ◽

Keyword(s):

B Cells ◽

B Cell ◽

Cell Receptor ◽

Memory B Cells ◽

Effector Function ◽

B Cell Receptor ◽

Receptor Signaling ◽

B Cell Receptor Signaling ◽

Cell Receptor Signaling

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Notch1 enhances B-cell receptor-induced apoptosis in mature activated B cells without affecting cell cycle progression and surface IgM expression

Cell Death and Differentiation ◽

10.1038/sj.cdd.4401253 ◽

2003 ◽

Vol 10 (7) ◽

pp. 833-844 ◽

Cited By ~ 20

Author(s):

S Romer ◽

U Saunders ◽

H-M Jäck ◽

B M Jehn

Keyword(s):

Cell Cycle ◽

B Cells ◽

B Cell ◽

Cell Cycle Progression ◽

Cell Receptor ◽

B Cell Receptor ◽

Cycle Progression ◽

Induced Apoptosis ◽

Activated B Cells

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Silencing of B Cell Receptor Signals in Human Naive B Cells

Journal of Experimental Medicine ◽

10.1084/jem.20020881 ◽

2002 ◽

Vol 196 (10) ◽

pp. 1291-1305 ◽

Cited By ~ 43

Author(s):

Niklas Feldhahn ◽

Ines Schwering ◽

Sanggyu Lee ◽

Maria Wartenberg ◽

Florian Klein ◽

...

Keyword(s):

Gene Expression ◽

B Cells ◽

B Cell ◽

Cell Receptor ◽

Memory B Cells ◽

B Cell Receptor ◽

Functional Assay ◽

Hematopoietic Stem ◽

Large Group ◽

Bcr Signaling

To identify changes in the regulation of B cell receptor (BCR) signals during the development of human B cells, we generated genome-wide gene expression profiles using the serial analysis of gene expression (SAGE) technique for CD34+ hematopoietic stem cells (HSCs), pre-B cells, naive, germinal center (GC), and memory B cells. Comparing these SAGE profiles, genes encoding positive regulators of BCR signaling were expressed at consistently lower levels in naive B cells than in all other B cell subsets. Conversely, a large group of inhibitory signaling molecules, mostly belonging to the immunoglobulin superfamily (IgSF), were specifically or predominantly expressed in naive B cells. The quantitative differences observed by SAGE were corroborated by semiquantitative reverse transcription–polymerase chain reaction (RT-PCR) and flow cytometry. In a functional assay, we show that down-regulation of inhibitory IgSF receptors and increased responsiveness to BCR stimulation in memory as compared with naive B cells at least partly results from interleukin (IL)-4 receptor signaling. Conversely, activation or impairment of the inhibitory IgSF receptor LIRB1 affected BCR-dependent Ca2+ mobilization only in naive but not memory B cells. Thus, LIRB1 and IL-4 may represent components of two nonoverlapping gene expression programs in naive and memory B cells, respectively: in naive B cells, a large group of inhibitory IgSF receptors can elevate the BCR signaling threshold to prevent these cells from premature activation and clonal expansion before GC-dependent affinity maturation. In memory B cells, facilitated responsiveness upon reencounter of the immunizing antigen may result from amplification of BCR signals at virtually all levels of signal transduction.

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