Translocation of the B cell receptor to lipid rafts is inhibited in B cells from BLV-infected, persistent lymphocytosis cattle

ABSTRACT Bovine leukemia virus (BLV), a retrovirus related to human T-cell leukemia virus types 1 and 2, can induce persistent nonneoplastic expansion of the CD5+ B-cell population, termed persistent lymphocytosis (PL). As in human CD5+ B cells, we report here that CD5 was physically associated with the B-cell receptor (BCR) in normal bovine CD5+ B cells. In contrast, in CD5+ B cells from BLV-infected PL cattle, CD5 was dissociated from the BCR. In B cells from PL cattle, apoptosis decreased when cells were stimulated with antibody to surface immunoglobulin M (sIgM), while in B cells from uninfected cattle, apoptosis increased after sIgM stimulation. The functional significance of the CD5-BCR association was suggested by experimental dissociation of the CD5-BCR interaction by cross-linking of CD5. This caused CD5+ B cells from uninfected animals to decrease apoptosis when stimulated with anti-sIgM. In contrast, in CD5+ B cells from PL animals, in which CD5 was already dissociated from the BCR, there was no statistically significant change in apoptosis when CD5 was cross-linked and the cells were stimulated with anti-sIgM. Disruption of CD5-BCR interactions and subsequent decreased apoptosis and increased survival in antigenically stimulated B cells may be a mechanism of BLV-induced PL.

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Faculty Opinions recommendation of Constitutive expression of the B7h ligand for inducible costimulator on naive B cells is extinguished after activation by distinct B cell receptor and interleukin 4 receptor-mediated pathways and can be rescued by CD40 signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1007572.115357 ◽

2002 ◽

Author(s):

Vincent Ling

Keyword(s):

B Cells ◽

B Cell ◽

Constitutive Expression ◽

Cell Receptor ◽

B Cell Receptor ◽

Interleukin 4 ◽

Inducible Costimulator ◽

Interleukin 4 Receptor

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Delivery of B Cell Receptor–internalized Antigen to Endosomes and Class II Vesicles

Journal of Experimental Medicine ◽

10.1084/jem.186.8.1299 ◽

1997 ◽

Vol 186 (8) ◽

pp. 1299-1306 ◽

Cited By ~ 31

Author(s):

James R. Drake ◽

Paul Webster ◽

John C. Cambier ◽

Ira Mellman

Keyword(s):

B Cells ◽

B Cell ◽

Antigen Processing ◽

Specific Antigen ◽

Cell Receptor ◽

Class Ii ◽

Time Frame ◽

B Cell Receptor ◽

Subcellular Compartment ◽

Endocytic Vesicles

B cell receptor (BCR)-mediated antigen processing is a mechanism that allows class II–restricted presentation of specific antigen by B cells at relatively low antigen concentrations. Although BCR-mediated antigen processing and class II peptide loading may occur within one or more endocytic compartments, the functions of these compartments and their relationships to endosomes and lysosomes remain uncertain. In murine B cells, at least one population of class II– containing endocytic vesicles (i.e., CIIV) has been identified and demonstrated to be distinct both physically and functionally from endosomes and lysosomes. We now demonstrate the delivery of BCR-internalized antigen to CIIV within the time frame during which BCR-mediated antigen processing and formation of peptide–class II complexes occurs. Only a fraction of the BCR-internalized antigen was delivered to CIIV, with the majority of internalized antigen being delivered to lysosomes that are largely class II negative. The extensive colocalization of BCR-internalized antigen and newly synthesized class II molecules in CIIV suggests that CIIV may represent a specialized subcellular compartment for BCR-mediated antigen processing. Additionally, we have identified a putative CIIV-marker protein, immunologically related to the Igα subunit of the BCR, which further illustrates the unique nature of these endocytic vesicles.

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Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells

Cellular and Molecular Life Sciences ◽

10.1007/s00018-021-03910-x ◽

2021 ◽

Author(s):

Sarah Wilmore ◽

Karly-Rai Rogers-Broadway ◽

Joe Taylor ◽

Elizabeth Lemm ◽

Rachel Fell ◽

...

Keyword(s):

B Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Mrna Translation ◽

Cell Receptor ◽

Memory B Cells ◽

B Cell Receptor ◽

Lymphocytic Leukemia ◽

Mrna Levels ◽

Mrna Stabilization

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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Expression of TASK‐2 and its upregulation by B cell receptor stimulation in WEHI‐231 mouse immature B cells

The FASEB Journal ◽

10.1096/fasebj.25.1_supplement.lb510 ◽

2011 ◽

Vol 25 (S1) ◽

Author(s):

Dong Hoon Shin

Keyword(s):

B Cells ◽

B Cell ◽

Cell Receptor ◽

B Cell Receptor ◽

Receptor Stimulation ◽

Wehi 231 ◽

Immature B Cells

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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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Faculty Opinions recommendation of B Cell Receptor and CD40 Signaling Are Rewired for Synergistic Induction of the c-Myc Transcription Factor in Germinal Center B Cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732604893.793573078 ◽

2020 ◽

Author(s):

Elizabeth Mellins ◽

Debopam Ghosh

Keyword(s):

Transcription Factor ◽

B Cells ◽

B Cell ◽

Germinal Center ◽

Cell Receptor ◽

B Cell Receptor ◽

Synergistic Induction ◽

Germinal Center B Cells

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Signatures of B Cell Receptor Repertoire Following Pneumocystis Infection

Frontiers in Microbiology ◽

10.3389/fmicb.2021.636250 ◽

2021 ◽

Vol 12 ◽

Author(s):

Han Sun ◽

Hu-Qin Yang ◽

Kan Zhai ◽

Zhao-Hui Tong

Keyword(s):

B Cells ◽

B Cell ◽

Single Cell ◽

Plasma Cells ◽

Somatic Hypermutation ◽

Cell Receptor ◽

B Cell Receptor ◽

Receptor Repertoire ◽

Elevated Expression ◽

Pneumocystis Infection

B cells play vital roles in host defense against Pneumocystis infection. However, the features of the B cell receptor (BCR) repertoire in disease progression remain unclear. Here, we integrated single-cell RNA sequencing and single-cell BCR sequencing of immune cells from mouse lungs in an uninfected state and 1–4 weeks post-infection in order to illustrate the dynamic nature of B cell responses during Pneumocystis infection. We identified continuously increased plasma cells and an elevated ratio of (IgA + IgG) to (IgD + IgM) after infection. Moreover, Pneumocystis infection was associated with an increasing naïve B subset characterized by elevated expression of the transcription factor ATF3. The proportion of clonal expanded cells progressively increased, while BCR diversity decreased. Plasma cells exhibited higher levels of somatic hypermutation than naïve B cells. Biased usage of V(D)J genes was observed, and the usage frequency of IGHV9-3 rose. Overall, these results present a detailed atlas of B cell transcriptional changes and BCR repertoire features in the context of Pneumocystis infection, which provides valuable information for finding diagnostic biomarkers and developing potential immunotherapeutic targets.

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