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| Open Access
A loss-of-adhesion CRISPR-Cas9 screening platform to identify cell adhesion-regulatory proteins and signaling pathways
Targeting integrin-mediated retention of malignant B cells in their protective microenvironment is an efficacious treatment for lymphoma and leukemia. Here, the authors present an unbiased loss-of-adhesion CRISPR screening method, identifying therapeutic targets for these B-cell malignancies.
- Martin F. M. de Rooij
- , Yvonne J. Thus
- & Marcel Spaargaren
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Article
| Open Access
Actomyosin-driven force patterning controls endocytosis at the immune synapse
The immune synapse promotes cellular information exchange but the role of biophysical forces in synapse function is unclear. Here, the authors show that B cells exert two types of forces, a centripetal myosin II-driven force and a central actin protrusive force at the site of antigen extraction.
- Anita Kumari
- , Judith Pineau
- & Paolo Pierobon
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Article
| Open Access
Galectin-9 suppresses B cell receptor signaling and is regulated by I-branching of N-glycans
Leukocytes are coated with glycans that modulate immune function through interactions with lectins. Here, the authors characterize the N-glycan repertoire of human tonsillar B cells. They report that Gal-9 is an intrinsic regulator of B cell activation that may differentially modulate BCR signaling at steady state and within germinal centers due to expression of I-branched glycans.
- N. Giovannone
- , J. Liang
- & C. J. Dimitroff
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| Open Access
Galectin-9 binds IgM-BCR to regulate B cell signaling
The galectin family of secreted lectins are important regulators of immune cell function; however, their role in B cell responses is poorly understood. Here, the authors identify IgM-BCR as a ligand for galectin-9. In resting naive cells, they show that galectin-9 mediates a close association between IgM and CD22.
- Anh Cao
- , Nouf Alluqmani
- & Bebhinn Treanor
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Article
| Open Access
The H2B deubiquitinase Usp22 promotes antibody class switch recombination by facilitating non-homologous end joining
Class switch recombination (CSR) requires break and repair of immunoglobulin DNA. Here the authors show that the histone deubiquitinase Usp22 is involved in V(D)J recombination and CSR of IgG and IgE, but not IgA, and that IgG CSR is dependent on the canonical c-NHEJ pathway, whereas IgA CSR is more dependent on the alternative A-EJ pathway.
- Conglei Li
- , Thergiory Irrazabal
- & Alberto Martin
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Article
| Open Access
Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations
An efficient HIV-1 vaccine will likely depend on eliciting broadly neutralizing antibodies (bnAb). Here the authors analyze the B cell repertoire in macaques and knock-in mice in response to sequential immunization with Env variants that induce a bnAb targeting the CD4-binding site of Env in a HIV-1 infected individual.
- Wilton B. Williams
- , Jinsong Zhang
- & Laurent Verkoczy
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Article
| Open Access
Accurate immune repertoire sequencing reveals malaria infection driven antibody lineage diversification in young children
Somatic hypermutation of antibodies can occur in infants but are difficult to track. Here the authors present a new method called MIDCIRS for deep quantitative repertoire sequencing with few cells, and show infants as young as 3 months can expand antibody lineage complexity in response to malaria infection.
- Ben S. Wendel
- , Chenfeng He
- & Ning Jiang
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Article
| Open Access
Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia
Chronic lymphocytic leukaemia (CLL) is characterized by cell-autonomous B-cell receptor (BcR)-mediated signalling of neoplastic B lymphocytes. Here the authors unveil the structural basis and diversity of activatory homotypic BcR contacts and link them with CLL heterogeneity and the clinical outcome.
- Claudia Minici
- , Maria Gounari
- & Massimo Degano
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Article
| Open Access
Temporal regulation of Lsp1 O-GlcNAcylation and phosphorylation during apoptosis of activated B cells
B cell receptor (BCR) activation can trigger signalling causing apoptosis in order to eliminate auto-reactive B cells. Here the authors show that the O-GlcNAcylation and phosphorylation of lymphocyte-specific protein-1 are involved in a switch that regulates the initiation of apoptosis induced by BCR cross-linking.
- Jung-Lin Wu
- , Hsin-Yi Wu
- & Kuo-I. Lin
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Article
| Open Access
Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics
The homeobox NKX2 family of transcriptional factors has been shown to regulate fundamental developmental processes. Here, the authors show that NKX2-3 is a bona fideoncogenic driver in marginal-zone B-cell lymphoma and that it promotes lymphomagenesis by shaping lymphocyte dynamics and promoting BCR signalling.
- Eloy F. Robles
- , Maria Mena-Varas
- & Jose A. Martinez-Climent
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Article
| Open Access
Individual heritable differences result in unique cell lymphocyte receptor repertoires of naïve and antigen-experienced cells
The diversity of antigen receptor specificities is largely generated by random recombination of its segments. Here the authors show, by genetic comparison of monozygotic twin lymphocyte subsets, that individual genetic and epigenetic biases also contribute to the shape of the B and T cell repertoires.
- Florian Rubelt
- , Christopher R. Bolen
- & Mark M. Davis
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Article
| Open Access
Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice
The induction of broadly neutralizing antibodies (bNAbs) is a goal of HIV-1 vaccine research. Here the authors demonstrate the ability of an HIV Env-derived immunogen to bind germline precursors of a class of bNAbs and to activate the corresponding B cells in a knock-in mouse model
- Andrew T. McGuire
- , Matthew D. Gray
- & Leonidas Stamatatos
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Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding VH81X-expressing B cells
Self-reactive B cells producing autoantibodies are associated with autoimmune conditions. Here, the authors show that in mice lacking the surrogate light chain, which normally assembles with antibody heavy chain to form a pre-B-cell receptor, the autoantibody-producing cells derive from germinal centres.
- Ola Grimsholm
- , Weicheng Ren
- & Inga-Lill Mårtensson
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Pre-B cell receptor binding to galectin-1 modifies galectin-1/carbohydrate affinity to modulate specific galectin-1/glycan lattice interactions
Galectin-1 (GAL1) is a secreted protein that binds to glycans and to the pre-B-cell receptor (pre-BCR). Here Bonzi et al. show that pre-BCR binding to GAL1 causes a conformational change in the GAL1 carbohydrate-binding site to inhibit binding to selected glycans.
- Jeremy Bonzi
- , Olivier Bornet
- & Latifa Elantak
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Article
| Open Access
Toll-like receptor ligands sensitize B-cell receptor signalling by reducing actin-dependent spatial confinement of the receptor
Microbial pathogens can activate both innate and adaptive receptors, and integration of these signals may enhance the sensitivity of the immune response. Freeman et al. show that innate microbial cues sensitize B cells to antigen by increasing actin dynamics and reducing the actin-dependent confinement of the B-cell receptor.
- Spencer A. Freeman
- , Valentin Jaumouillé
- & Michael R. Gold
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| Open Access
The immunoglobulin tail tyrosine motif upgrades memory-type BCRs by incorporating a Grb2-Btk signalling module
How class-switched memory B cells signal to respond robustly to recurring pathogens is incompletely understood. Here the authors show that immunoglobulin tail tyrosine motifs in membrane-bound immunoglobulin isotypes of class-switched cells amplify signalling in memory B cells, in a mechanism that includes distinct kinases and adaptor proteins.
- Niklas Engels
- , Lars M. König
- & Jürgen Wienands
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Germinal centre protein HGAL promotes lymphoid hyperplasia and amyloidosis via BCR-mediated Syk activation
The human germinal centre-associated lymphoma gene is expressed in germinal centre B-lymphocytes; however, its function is unknown. Here the authors show that human germinal centre-associated lymphoma activates Syk kinase, leading to lymphoid hyperplasia and systemic reactive amyloid A amyloidosis in transgenic mice.
- Isabel Romero-Camarero
- , Xiaoyu Jiang
- & Izidore S Lossos
MCT1-governed pyruvate metabolism is essential for antibody class-switch recombination through H3K27 acetylation