Coordinated changes in glycosylation regulate the germinal centre through CD22

AbstractGerminal centres (GC) are sites of B-cell expansion and selection, which are essential for antibody affinity maturation. Compared to naive follicular B-cells, GC B-cells have several notable changes in their cell surface glycans. While these changes are routinely used to identify the GC, functional roles for these changes have yet to be ascribed. Detection of GCs by the antibody GL7 reflects a reduction in the glycan ligands for CD22, which is an inhibitory co-receptor of the B-cell receptor (BCR). To test a functional role for downregulated CD22 ligands in the GC, we generated a mouse model that maintains CD22 ligands on GC B-cells. With this model, we demonstrate that glycan remodeling is crucial for proper GC B-cell response, including plasma cell output and affinity maturation of antibodies. The defect we observe in this model is dependent on CD22, highlighting that coordinated downregulation of CD22 ligands on B cells plays a critical function in the GC. Collectively, our study uncovers a crucial role for glycan remodeling and CD22 in B-cell fitness in the GC.

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BCR Affinity Influences T-B Interactions and B Cell Development in Secondary Lymphoid Organs

Frontiers in Immunology ◽

10.3389/fimmu.2021.703918 ◽

2021 ◽

Vol 12 ◽

Author(s):

Alec J. Wishnie ◽

Tzippora Chwat-Edelstein ◽

Mary Attaway ◽

Bao Q. Vuong

Keyword(s):

B Cells ◽

B Cell ◽

Cell Receptor ◽

Cell Development ◽

B Cell Development ◽

Affinity Maturation ◽

B Cell Receptor ◽

Specific Cell ◽

High Affinity ◽

Tfh Cells

B cells produce high-affinity immunoglobulins (Igs), or antibodies, to eliminate foreign pathogens. Mature, naïve B cells expressing an antigen-specific cell surface Ig, or B cell receptor (BCR), are directed toward either an extrafollicular (EF) or germinal center (GC) response upon antigen binding. B cell interactions with CD4+ pre-T follicular helper (pre-Tfh) cells at the T-B border and effector Tfh cells in the B cell follicle and GC control B cell development in response to antigen. Here, we review recent studies demonstrating the role of B cell receptor (BCR) affinity in modulating T-B interactions and the subsequent differentiation of B cells in the EF and GC response. Overall, these studies demonstrate that B cells expressing high affinity BCRs preferentially differentiate into antibody secreting cells (ASCs) while those expressing low affinity BCRs undergo further affinity maturation or differentiate into memory B cells (MBCs).

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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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Vav proteins regulate peripheral B-cell survival

Blood ◽

10.1182/blood-2004-12-4894 ◽

2005 ◽

Vol 106 (7) ◽

pp. 2391-2398 ◽

Cited By ~ 33

Author(s):

Elena Vigorito ◽

Laure Gambardella ◽

Francesco Colucci ◽

Simon McAdam ◽

Martin Turner

Keyword(s):

B Cells ◽

B Cell ◽

Marginal Zone ◽

Cell Receptor ◽

Cross Linking ◽

Marginal Zone B Cells ◽

Survival Signal ◽

B Cell Survival ◽

Follicular B Cells ◽

Deficient Mice

AbstractMice lacking all 3 Vav proteins fail to produce significant numbers of recirculating follicular or marginal zone B cells. Those B cells that do mature have shortened lifespans. The constitutive nuclear factor-kappaB (NF-κB) activity of resting naive B cells required Vav function and expression of cellular reticuloendotheliosis (c-Rel). Rel-A was reduced in Vav-deficient B cells. Furthermore, expression of the NF-κB-regulated antiapoptotic genes A1 and Bcl-2 was reduced in mature Vav-deficient B cells. Overexpression of Bcl-2 restored the number of mature follicular B cells in the spleens of Vav-deficient mice. When activated by B-cell receptor (BCR) cross-linking, Vav-deficient B cells failed to activate NF-κB. Vav proteins thus regulate an NF-κB-dependent survival signal in naive B cells and are required for NF-κB function after BCR cross-linking.

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