Division of labor during primary humoral immunity

Swanson, Cristina L.; Pelanda, Roberta; Torres, Raul M.

doi:10.1007/s12026-012-8372-9

Cited by 20 publications

(20 citation statements)

References 116 publications

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“…In addition, B cells are critical regulators of the immune system. Apart from the immune regulatory function of antibody and antibody–antigen complexes, B cells can shape the functions of other immune cells by presenting antigen, providing co-stimulations, and secreting cytokines [1-4]. Because of their essential roles in immune protection, complex mechanisms have been evolved to regulate the functions of B cells, in order to mount the optimal antibody responses and to efficiently cooperate with other immune cells and systems during infections.…”

Section: Introductionmentioning

confidence: 99%

The pivotal position of the actin cytoskeleton in the initiation and regulation of B cell receptor activation

Song

Liu

Upadhyaya

2014

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The actin cytoskeleton is a dynamic cellular network known for its function in cell morphology and motility. Recent studies using high resolution and real time imaging techniques have revealed that actin plays a critical role in signal transduction, primarily by modulating the dynamics and organization of membrane-associated receptors and signaling molecules. This review summarizes what we have learned so far about a regulatory niche of the actin cytoskeleton in the signal transduction of the B cell receptor (BCR). The activation of the BCR is initiated and regulated by a close coordination between the dynamics of surface BCRs and the cortical actin network. The actin cytoskeleton is involved in regulating the signaling threshold of the BCR to antigenic stimulation, the kinetics and amplification of BCR signaling activities, and the timing and kinetics of signaling downregulation. Actin exerts its regulatory function by controlling the kinetics, magnitude, subcellular location, and nature of BCR clustering and BCR signaling complex formation at every stage of signaling. The cortical actin network is remodeled by initial detachment from the plasma membrane, disassembly and subsequent reassembly into new actin structures in response to antigenic stimulation. Signaling responsive actin regulators translate BCR stimulatory and inhibitory signals into a series of actin remodeling events, which enhance signaling activation and down-regulation by modulating the lateral mobility and spatial organization of surface BCR. The mechanistic understanding of actinmediated signaling regulation in B cells will help us explore B cell-specific manipulations of the actin cytoskeleton as treatments for B cell-mediated autoimmunity and B cell cancer. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters.

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Section: Introductionmentioning

confidence: 99%

The pivotal position of the actin cytoskeleton in the initiation and regulation of B cell receptor activation

Song

Liu

Upadhyaya

2014

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…However, the mutant cells exhibited increased turnover as well as functional deficiencies upon activation, suggesting that canonical NF-κB signals contribute to their long-term persistence and functional fitness. (1). Two receptors, the B-cell antigen receptor (BCR) and B-cell activating factor of the tumor necrosis factor family receptor (BAFFR), have been shown to control the generation and/or persistence of mature B cells critically (2)(3)(4)(5).…”

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confidence: 99%

Canonical NF-κB signaling is uniquely required for the long-term persistence of functional mature B cells

Derudder

Herzog

Labi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Although canonical NF-κB signaling is crucial to generate a normal mature B-cell compartment, its role in the persistence of resting mature B cells is controversial. To resolve this conflict, we ablated NF-κB essential modulator (NEMO) and IκB kinase 2 (IKK2), two essential mediators of the canonical pathway, either early on in B-cell development or specifically in mature B cells. Early ablation severely inhibited the generation of all mature B-cell subsets, but follicular B-cell numbers could be largely rescued by ectopic expression of B-cell lymphoma 2 (Bcl2), despite a persisting block at the transitional stage. Marginal zone (MZ) B and B1 cells were not rescued, indicating a possible role of canonical NF-κB signals beyond the control of cell survival in these subsets. When canonical NF-κB signaling was ablated specifically in mature B cells, the differentiation and/or persistence of MZ B cells was still abrogated, but follicular B-cell numbers were only mildly affected. However, the mutant cells exhibited increased turnover as well as functional deficiencies upon activation, suggesting that canonical NF-κB signals contribute to their long-term persistence and functional fitness. Numerous stimuli activate the NF-κB signaling pathways in mature B cells. In mammals, the NF-κB family of transcription factors comprises five members (RelA, RelB, c-Rel, NF-κB1, and NF-κB2) whose activation is initiated by two major signaling pathways (5). The canonical pathway depends on the IκB kinase (IKK) complex, consisting of the structural protein NF-κB essential modulator (NEMO) and the IκB kinases IKK1 and IKK2. This complex triggers the degradation of a specific set of inhibitors of NF-κB and the induction of dimers containing RelA and/or c-Rel. The canonical pathway regulates NF-κB activation downstream of the BCR (5). The stimulation of the alternative pathway, mediated by NF-κB-inducing kinase and IKK1, leads to the partial proteolysis of the inhibitory precursor NF-κB2 and the activation of dimers containing RelB and/or the processed form of NF-κB2 through another set of receptors, including BAFFR (4).There is abundant evidence for a critical role of the canonical pathway in the generation and/or maintenance of mature B cells. The ablation of NEMO or IKK2 in the B-cell lineage, as well as conditional replacement of the latter by a kinase-dead IKK2, impaired the generation of the three mature B subsets and transitional 2 (T2) cells, a developmental stage preceding the mature stage (6-9). In the case of the kinase-dead IKK2, some mutant cells made it into the mature compartment but were completely outcompeted by WT cells over a period of 4 wk, upon blockade of B-cell generation in the bone marrow (6). Mechanistically, tonic BCR signaling could increase the production of NF-κB2 via canonical NF-κB activation in T2 and follicular B cells, sensitizing B cells to the prosurvival effect of BAFFR (10).However, other work suggested that canonical signals downstream of the BCR may not be critical for the maintenance of mature fo...

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“…The antibody response to HIV gp120 has been studied for decades, largely through analysis of serological data from chronically infected subjects. The antibody response to physiological pathogens normally involves a concerted effort among different types of B cells (15); thus, we set out to investigate the extent to which B-cell subsets are capable of participating in the primary HIV antibody response not only to better understand why this response is typically nonprotective, but also to inform directions for vaccine design.…”

Section: Resultsmentioning

confidence: 99%

“…Accomplishing this may require the specific participation of different B-cell subsets. The antibody response to physiological pathogens is a cooperative effort between different B-cell subpopulations (15). The major B-cell populations, CD21 + CD23 + follicular (FO) cells in mice and IgD + CD27 -naïve B cells in humans, require the help of cognate T cells to respond to protein antigens to produce class-switched, affinity-matured antibodies and memory B cells, a process that takes time to develop.…”

mentioning

confidence: 99%

Mouse marginal zone B cells harbor specificities similar to human broadly neutralizing HIV antibodies

Pujanauski

Janoff²,

McCarter

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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A series of potent, broadly neutralizing HIV antibodies have been isolated from B cells of HIV-infected individuals. VRC01 represents a subset of these antibodies that mediate neutralization with a restricted set of IGHV genes. The memory B cells expressing these antibodies were isolated years after infection; thus, the B-cell subpopulation from which they originated and the extent of participation in the initial HIV antibody response, if any, are unclear. Here we evaluated the frequency of anti-gp120 B cells in follicular (FO) and marginal zone (MZ) B-cell compartments of naïve WT mice and comparable human populations in uninfected individuals. We found that in non-HIV-exposed humans and mice, the majority of gp120-reactive B cells are of naïve and FO phenotype, respectively. Murine FO B cells express a diverse antibody repertoire to recognize gp120. In contrast, mouse MZ B cells recognize gp120 less frequently but preferentially use IGHV1-53 to encode gp120-specific antibodies. Notably, IGHV1-53 shows high identity to human IGHV1-2*02, which has been repeatedly found to encode broadly neutralizing mutated HIV antibodies, such as VRC01. Finally, we show that human MZ-like B cells express IGHV1-2*02, and that IGHV1-53 expression is enriched in mouse MZ B cells. These data suggest that efforts toward developing an HIV vaccine might consider eliciting protective HIV antibody responses selectively from alternative B-cell populations harboring IGHV gene segments capable of producing protective antibodies.B-cell subsets | virus | germ line | polyreactive

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Division of labor during primary humoral immunity

Cited by 20 publications

References 116 publications

The pivotal position of the actin cytoskeleton in the initiation and regulation of B cell receptor activation

The pivotal position of the actin cytoskeleton in the initiation and regulation of B cell receptor activation

Canonical NF-κB signaling is uniquely required for the long-term persistence of functional mature B cells

Mouse marginal zone B cells harbor specificities similar to human broadly neutralizing HIV antibodies

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