scholarly journals Arp2/3 complex-driven spatial patterning of the BCR enhances immune synapse formation, BCR signaling and cell activation

2018 ◽  
Author(s):  
Madison Bolger-Munro ◽  
Kate Choi ◽  
Joshua Scurll ◽  
Libin Abraham ◽  
Rhys Chappell ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Synapse Formation ◽  
Critical Role ◽  
Transcriptional Responses ◽  
Immune Synapse ◽  
Cell Responses ◽  
Bcr Signaling ◽  
B Cell Responses

AbstractWhen B cells encounter antigens on the surface of an antigen-presenting cell (APC), B cell receptors (BCRs) are gathered into microclusters that recruit signaling enzymes. These microclusters then move centripetally and coalesce into the central supramolecular activation cluster of an immune synapse. The mechanisms controlling BCR organization during immune synapse formation, and how this impacts BCR signaling, are not fully understood. We show that this coalescence of BCR microclusters depends on the actin-related protein 2/3 (Arp2/3) complex, which nucleates branched actin networks. Moreover, in murine B cells this dynamic spatial reorganization of BCR microclusters amplifies proximal BCR signaling reactions and enhances the ability of membrane-associated antigens to induce transcriptional responses and proliferation. Our finding that Arp2/3 complex activity is important for B cell responses to spatially-restricted membrane-bound antigens, but not for soluble antigens, highlights a critical role for Arp2/3 complex-dependent actin remodelling in B cell responses to APC-bound antigens.

scholarly journals Arp2/3 complex-driven spatial patterning of the BCR enhances immune synapse formation, BCR signaling and B cell activation

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Madison Bolger-Munro ◽  
Kate Choi ◽  
Joshua M Scurll ◽  
Libin Abraham ◽  
Rhys S Chappell ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Synapse Formation ◽  
Critical Role ◽  
Transcriptional Responses ◽  
Immune Synapse ◽  
Cell Responses ◽  
Bcr Signaling ◽  
B Cell Responses

When B cells encounter antigens on the surface of an antigen-presenting cell (APC), B cell receptors (BCRs) are gathered into microclusters that recruit signaling enzymes. These microclusters then move centripetally and coalesce into the central supramolecular activation cluster of an immune synapse. The mechanisms controlling BCR organization during immune synapse formation, and how this impacts BCR signaling, are not fully understood. We show that this coalescence of BCR microclusters depends on the actin-related protein 2/3 (Arp2/3) complex, which nucleates branched actin networks. Moreover, in murine B cells, this dynamic spatial reorganization of BCR microclusters amplifies proximal BCR signaling reactions and enhances the ability of membrane-associated antigens to induce transcriptional responses and proliferation. Our finding that Arp2/3 complex activity is important for B cell responses to spatially restricted membrane-bound antigens, but not for soluble antigens, highlights a critical role for Arp2/3 complex-dependent actin remodeling in B cell responses to APC-bound antigens.

scholarly journals Extrafollicular B cell activation by marginal zone dendritic cells drives T cell–dependent antibody responses

2012 ◽  
Vol 209 (10) ◽  
pp. 1825-1840 ◽  
Author(s):  
Craig P. Chappell ◽  
Kevin E. Draves ◽  
Natalia V. Giltiay ◽  
Edward A. Clark
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Marginal Zone ◽  
Receptor Expression ◽  
B Cell Activation ◽  
Cell Responses ◽  
B Cell Responses

Dendritic cells (DCs) are best known for their ability to activate naive T cells, and emerging evidence suggests that distinct DC subsets induce specialized T cell responses. However, little is known concerning the role of DC subsets in the initiation of B cell responses. We report that antigen (Ag) delivery to DC-inhibitory receptor 2 (DCIR2) found on marginal zone (MZ)–associated CD8α− DCs in mice leads to robust class-switched antibody (Ab) responses to a T cell–dependent (TD) Ag. DCIR2+ DCs induced rapid up-regulation of multiple B cell activation markers and changes in chemokine receptor expression, resulting in accumulation of Ag-specific B cells within extrafollicular splenic bridging channels as early as 24 h after immunization. Ag-specific B cells primed by DCIR2+ DCs were remarkably efficient at driving naive CD4 T cell proliferation, yet DCIR2-induced responses failed to form germinal centers or undergo affinity maturation of serum Ab unless toll-like receptor (TLR) 7 or TLR9 agonists were included at the time of immunization. These results demonstrate DCIR2+ DCs have a unique capacity to initiate extrafollicular B cell responses to TD Ag, and thus define a novel division of labor among splenic DC subsets for B cell activation during humoral immune responses.

scholarly journals FcRL4 acts as an adaptive to innate molecular switch dampening BCR signaling and enhancing TLR signaling

Blood ◽  
2011 ◽  
Vol 118 (24) ◽  
pp. 6332-6341 ◽  
Author(s):  
Hae Won Sohn ◽  
Peter D. Krueger ◽  
Randall S. Davis ◽  
Susan K. Pierce
Keyword(s):  
B Cells ◽  
B Cell ◽  
Synapse Formation ◽  
Molecular Switch ◽  
Lymphoid Tissues ◽  
Immune Synapse ◽  
Chronic Antigenic Stimulation ◽  
Bcr Signaling ◽  
Cd69 Expression ◽  
Human B Cell

Abstract Fc receptor–like 4 (FcRL4) is expressed on the surface of a subset of memory B cells (MBCs) located at sites of invading pathogens in mucosal lymphoid tissues in healthy individuals. Recently, FcRL4+ MBCs were shown to be greatly increased in number in the peripheral blood of HIV-infected viremic individuals, in whom they are associated with B-cell exhaustion, and in individuals chronically reinfected with malaria. In the present study, we provide evidence that the expression of FcRL4 in human B-cell lines disrupts immune synapse formation and blocks antigen-induced BCR signaling at the point of Syk phosphorylation, blocking downstream activation of PLC-γ2 and Vav and the induction of calcium responses and CD69 expression. FcRL4 functions by ligation-independent mechanisms that require the 3 tyrosine residues in its cytoplasmic domain and involves its phosphorylation and association with the tyrosine phosphatases SHP-1 and SHP-2. Remarkably, FcRL4 is concentrated in endosomes after treatment with the TLR9 agonist CpG and enhances signaling through TLR9, as measured by increased expression of CD23. These findings suggest that FcRL4 may act as a molecular switch in B cells to dampen adaptive immune signaling and enhance innate signaling in response to chronic antigenic stimulation.

scholarly journals Type 1 interferon supports B cell responses to polysaccharide antigens but is not required for MPL/TDCM adjuvant effects on innate B cells

2021 ◽  
Author(s):  
Ariel Spurrier ◽  
Jamie Jennings-Gee ◽  
Karen Haas
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Lipid A ◽  
Type I ◽  
Type I Ifn ◽  
Cell Responses ◽  
Monophosphoryl Lipid A ◽  
B Cell Responses ◽  
Adjuvant Effects

We previously described monophosphoryl lipid A (MPL) and synthetic cord factor, trehalose-6,6-dicorynomycolate (TDCM) significantly increases antibody (Ab) responses to T cell independent type 2 antigens (TI-2 Ags) in a manner dependent on B cell-intrinsic TLR4 expression as well as MyD88 and TRIF adapter proteins. Given the requirement for TRIF in optimal MPL/TDCM adjuvant effects and the capacity of MPL to drive type I IFN production, we aimed to investigate the extent to which adjuvant effects on TI-2 Ab responses depend on type I IFN receptor (IFNAR) signaling. We found IFNAR-/- mice had impaired early TI-2 Ag-induced B cell activation and expansion and that B cell-intrinsic type I IFN signaling on B cells was essential for normal antibody responses to TI-2 Ags, including haptenated Ficoll and the pneumococcal vaccine, Pneumovax23. However, MPL/TDCM significantly increased TI-2 IgM and IgG responses in IFNAR-/- mice. MPL/TDCM enhanced TI-2 Ab production primarily by activating innate B cells (B-1b and splenic CD23- B cells) as opposed to CD23+ enriched follicular B cells. In summary, our study highlights an important role for type I IFN in supporting early B cell responses to TI-2 Ags through B cell-expressed IFNAR, but nonetheless demonstrates an MPL/TDCM adjuvant significantly increases TI-2 Ab responses independently of type I IFN signaling and does so by predominantly supporting increased polysaccharide-specific Ab production by innate B cell populations.

scholarly journals Requirement for three signals in "T-independent" (lipopolysaccharide-induced) as well as in T-dependent B cell responses.

1982 ◽  
Vol 155 (3) ◽  
pp. 666-680 ◽  
Author(s):  
R H Zubler ◽  
A L Glasebrook
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
B Cell Activation ◽  
Cell Responses ◽  
Surface Immunoglobulin ◽  
Culture Cells ◽  
B Cell Responses ◽  
Helper Factor ◽  
To Receive

The requirements for different activation signals in the generation of plaque-forming cell (PFC) responses by positively selected B (surface immunoglobulin-positive) cells were analyzed in low-density cultures to minimize the possible effects of contaminating T cells. Using this system, it is demonstrated that not only in T helper cell (TH)-dependent but also in lipopolysaccharide (LPS)-dependent (i.e., so-called T-independent) PFC responses, the resting B cells have to receive at least three different signals: (a) a major histocompatibility complex (MHC)-specific TH signal that can be bypassed by LPS, (b) an antigen signal, and (c) a second TH signal medicated by MHC- and antigen-unspecific helper factor(s) for B cell responses (BHF) that cannot by bypassed by LPS. Specifically, contact of surface immunoglobulin-positive cells with cloned allo-I-A-specific TH or LPS induced a polyclonal PFC response without significant proliferation, whereas contact with BHF alone (obtained as supernatants from different cloned TH, EL-4 thymoma cells, or secondary mixed leukocyte culture cells) had no effect. Only when LPS, antigen, and BHF, or, alternatively, allo-TH (producing themselves BHF) and antigen were present did clonally expanded PFC responses occur. Thus, the data indicate that both an LPS (or specific TH) signal and an antigen signal are required to render the B cells responsive to BHF. BHF seems to act essentially as a nonspecific growth factor, whereas differentiation into antibody-secreting cells appears to be a preprogrammed consequence of B cell activation by an LPS or specific TH signal.

scholarly journals Targeting Vaccine-Induced Extrafollicular Pathway of B Cell Differentiation Improves Rabies Postexposure Prophylaxis

2017 ◽  
Vol 91 (8) ◽  
Author(s):  
Shannon L. Haley ◽  
Evgeni P. Tzvetkov ◽  
Samantha Meuwissen ◽  
Joseph R. Plummer ◽  
James P. McGettigan
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Antibody Responses ◽  
B Cell Differentiation ◽  
B Cell Activation ◽  
Postexposure Prophylaxis ◽  
Effective Prevention ◽  
Cell Responses ◽  
B Cell Responses

ABSTRACT Vaccine-induced B cells differentiate along two pathways. The follicular pathway gives rise to germinal centers (GCs) that can take weeks to fully develop. The extrafollicular pathway gives rise to short-lived plasma cells (PCs) that can rapidly secrete protective antibodies within days of vaccination. Rabies virus (RABV) postexposure prophylaxis (PEP) requires rapid vaccine-induced humoral immunity for protection. Therefore, we hypothesized that targeting extrafollicular B cell responses for activation would improve the speed and magnitude of RABV PEP. To test this hypothesis, we constructed, recovered, and characterized a recombinant RABV-based vaccine expressing murine B cell activating factor (BAFF) (rRABV-mBAFF). BAFF is an ideal molecule to improve early pathways of B cell activation, as it links innate and adaptive immunity, promoting potent B cell responses. Indeed, rRABV-mBAFF induced a faster, higher antibody response in mice and enhanced survivorship in PEP settings compared to rRABV. Interestingly, rRABV-mBAFF and rRABV induced equivalent numbers of GC B cells, suggesting that rRABV-mBAFF augmented the extrafollicular B cell pathway. To confirm that rRABV-mBAFF modulated the extrafollicular pathway, we used a signaling lymphocytic activation molecule (SLAM)-associated protein (SAP)-deficient mouse model. In response to antigen, SAP-deficient mice form extrafollicular B cell responses but do not generate GCs. rRABV-mBAFF induced similar anti-RABV antibody responses in SAP-deficient and wild-type mice, demonstrating that BAFF modulated immunity through the extrafollicular and not the GC B cell pathway. Collectively, strategies that manipulate pathways of B cell activation may facilitate the development of a single-dose RABV vaccine that replaces current complicated and costly RABV PEP. IMPORTANCE Effective RABV PEP is currently resource- and cost-prohibitive in regions of the world where RABV is most prevalent. In order to diminish the requirements for rabies immunoglobulin (RIG) and multiple vaccinations for effective prevention of clinical rabies, a more rapidly protective vaccine is needed. This work presents a successful approach to rapidly generate antibody-secreting PCs in response to vaccination by targeting the extrafollicular B cell pathway. We demonstrate that the improved early antibody responses induced by rRABV-mBAFF confer improved protection against RABV in a PEP model. Significantly, activation of the early extrafollicular B cell pathway, such as that demonstrated here, could improve the efficacy of vaccines targeting other pathogens against which rapid protection would decrease morbidity and mortality.

CXCL13/CXCR5 signaling enhances BCR-triggered B-cell activation by shaping cell dynamics

Blood ◽  
2011 ◽  
Vol 118 (6) ◽  
pp. 1560-1569 ◽  
Author(s):  
Julia Sáez de Guinoa ◽  
Laura Barrio ◽  
Mario Mellado ◽  
Yolanda R. Carrasco
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Synapse Formation ◽  
Behavior Pattern ◽  
Lymphocyte Function ◽  
B Cell Activation ◽  
Cell Dynamics ◽  
Membrane Ruffling ◽  
Bcr Signaling

Abstract Continuous migration of B cells at the follicle contrasts with their stable arrest after encounter with antigen. Two main ligand/receptor pairs are involved in these cell behaviors: the chemokine CXCL13/chemokine receptor CXCR5 and antigen/BCR. Little is known regarding the interplay between CXCR5 and BCR signaling in the modulation of B-cell dynamics and its effect on B-cell activation. We used a 2-dimensional model to study B-cell migration and antigen recognition in real time, and found that BCR signaling strength alters CXCL13-mediated migration, leading to a heterogeneous B-cell behavior pattern. In addition, we demonstrate that CXCL13/CXCR5 signaling does not impair BCR-triggered immune synapse formation and that CXCR5 is excluded from the central antigen cluster. CXCL13/CXCR5 signaling enhances BCR-mediated B-cell activation in at least 2 ways: (1) it assists antigen gathering at the synapse by promoting membrane ruffling and lymphocyte function–associated antigen 1 (LFA-1)–supported adhesion, and (2) it allows BCR signaling integration in motile B cells through establishment of LFA-1–supported migratory junctions. Both processes require functional actin cytoskeleton and non-muscle myosin II motor protein. Therefore, the CXCL13/CXCR5 signaling effect on shaping B-cell dynamics is an effective mechanism that enhances antigen encounter and BCR-triggered B-cell activation.

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