Siglec-G Regulates B1 Cell Survival and Selection

Jellusova, Julia; Düber, Sandra; Gückel, Eva; Binder, Christoph J.; Weiß, Siegfried; Voll, Reinhard; Nitschke, Lars

doi:10.4049/jimmunol.1001792

Cited by 57 publications

(64 citation statements)

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“…Besides a minor decrease in mature splenic B cells, we detected a strong reduction in peritoneal B1 cells in Akt1 Tg mice, which seems to reflect the enhanced sensitivity of B1 cells against altered BCR signals [34,35]. Interestingly, the decline of peritoneal B1 cells in younger Akt1 Tg mice was mainly due to a loss of B1b cells.…”

Section: Discussionmentioning

confidence: 67%

“…Since PI3K signaling has been proposed to regulate class switching [15,33], it is feasible that Akt1-mediated alterations in the expression levels of NF-κB, NFAT, and STAT5 influence the activity of activation-induced cytidine deaminase and other enzymes or of transcription factors involved in class switching. Further studies will also be needed to clarify whether besides altered BCR signaling, an altered in vivo migratory response or a survival advantage of Akt1 Tg B cells might contribute to the enhanced Ig production of Akt1 Tg B cells.Besides a minor decrease in mature splenic B cells, we detected a strong reduction in peritoneal B1 cells in Akt1 Tg mice, which seems to reflect the enhanced sensitivity of B1 cells against altered BCR signals [34,35]. Interestingly, the decline of peritoneal B1 cells in younger Akt1 Tg mice was mainly due to a loss of B1b cells.…”

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confidence: 67%

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Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

Pierau

Simma

et al. 2012

Eur J Immunol

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Ligation of the BCR induces a complex signaling network that involves activation ofAkt, a family of serine/threonine protein kinases associated with B-cell development, proliferation, and tumor formation. Here, we analyzed the effect of enhanced Akt1 signals on B-cell maturation and function. Unexpectedly, we found that peripheral B cells overexpressing Akt1 were less responsive to BCR stimuli. This correlated with a decrease in Ca 2+ -mobilization and proliferation, in an impaired activation of Erk1/2 and mammalian target of rapamycin (mTOR) kinases and poor mobilization of NFATc1 and NF-κB/p65 factors. In contrast, activation of STAT5 and migration of B cells toward the chemokine SDF1α was found to be enhanced. Akt1 Tg mice showed an altered maturation of peritoneal and splenic B1 B cells and an enhanced production of IgG1 and IgG3 upon immunization with the T-cell independent Ag TNP-Ficoll. Furthermore, mice homozygous for Tg Akt1 showed a severe block in the maturation of B-cell precursors in BM and a strong enrichment of plasma cells in spleen. Altogether, our data reveal that enhanced Akt1 signals modify BCR signaling strength and, thereby, B-cell development and effector function.Keywords: B cell r NFAT r PKB/Akt r SDF1α r STAT5 IntroductionIn the BM B-cell progenitors develop through defined stages of differentiation to immature B cells giving rise to follicular B2 (FO) B cells, marginal zone (MZ), and B1 B cells. These processes are controlled by the signal intensity arising from the pre-BCR or mature BCR, which activate similar sets of signaling molecules. The most proximal signaling events upon BCR ligation include Correspondence: Prof. Ursula H. Bommhardt e-mail: ursula.bommhardt@med.ovgu.de activation of the protein tyrosine kinases Lyn and Syk. A prominent substrate of Syk is the adaptor protein SLP65/BLNK, which recruits Bruton's tyrosine kinase, phospholipase Cγ2, and further signal proteins into supramolecular complexes that trigger the activation of multiple signaling pathways. Activated phospholipase Cγ2 cleaves the membrane lipid phosphatidylinositol-4, 5-bisphosphate (PIP2) to generate diacylglycerol and inositol-1,4,5-trisphosphate (IP3), two second messengers affecting the * These authors contributed equally to this work. Eur. J. Immunol. 2012. 42: 3381-3393 activation of PKC family members, MAPK activation, and the release of Ca 2+ from intracellular stores, which finally leads to influx of extracellular Ca 2+ . Elevated intracellular Ca 2+ -levels induce the activity of serine/threonine-specific phosphatase calcineurin and, in turn, a set of Ca 2+ -regulated transcription factors, in particular of NFAT and NF-κB factors that control various gene expression programs [1].An important signaling cascade induced after BCR engagement encompasses the lipid kinase family of class I PI3Ks [2][3][4]. Mature peripheral B cells lacking a BCR could be rescued from apoptosis by the ectopic expression of a constitutively active catalytic subunit of PI3K, indicating that PI3K signals support the surv...

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Section: Discussionmentioning

confidence: 67%

mentioning

confidence: 67%

Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

Pierau

Simma

et al. 2012

Eur J Immunol

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“…The higher B1a cell numbers in Siglec-G-deficient mice were shown to be due to a lower rate of apoptosis, compared with WT B1a cells (4). When cultivated in medium without cytokines, Siglec-G-R120E B1a cells showed a resistance to apoptosis similar to that in Siglec-G-deficient cells (Fig.…”

Section: Siglec-g Knockin Mice With a Mutated Ligand-binding Domain Smentioning

confidence: 68%

“…In addition, Siglec-G-deficient mice have a highly increased population of B1 cells, owing to decreased spontaneous apoptosis and a prolonged life span of these cells. A higher expression level of the transcription factor NFATc1 in Siglecg 2/2 B1 cells may be responsible for this effect (4). Siglec-G-deficient mice also show up to 10-fold increased natural IgM serum levels.…”

Section: The Journal Of Immunologymentioning

confidence: 96%

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The Ligand-Binding Domain of Siglec-G Is Crucial for Its Selective Inhibitory Function on B1 Cells

Hutzler

Özgör

Naito-Matsui

et al. 2014

The Journal of Immunology

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Siglec-G is an inhibitory receptor on B1 cells. Siglec-G–deficient mice show a large B1 cell expansion, owing to higher BCR-induced Ca2+ signaling and enhanced cellular survival. It was unknown why Siglec-G shows a B1 cell–restricted inhibitory function. With a new mAb we could show a comparable Siglec-G expression on B1 cells and conventional B2 cells. However, Siglec-G has a different ligand sialic acid–binding pattern on peritoneal B1 cells than on splenic B cells, and its sialic acid ligands are expressed differentially on these two B cell populations, suggesting that cis-ligand binding plays a crucial role on B1 cells. This observation was further studied by generation of Siglec-G knockin mice with a mutated ligand-binding domain. These mice show increased B1 cell numbers, increased B1 cell Ca2+ signaling, better B1 cell survival, and changes in the B1 cell Ig repertoire. These phenotypes are very similar to Siglec-G–deficient mice. The mutation of the ligand-binding domain of Siglec-G strongly reduces the Siglec-G–IgM association on the B cell surface. Thus, Siglec-G sialic acid–dependent binding to the BCR is crucial for the B1 cell–restricted inhibitory function of Siglec-G and is regulated in an opposite way to that of the related protein CD22 (Siglec-2) on B cells.

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Role of Calcium Signaling in B Cell Activation and Biology

Baba

Kurosaki

2015

Current Topics in Microbiology and Immunology

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Increase in intracellular levels of calcium ions (Ca2+) is one of the key triggering signals for the development of B cell response to the antigen. The diverse Ca2+ signals finely controlled by multiple factors participate in the regulation of gene expression, B cell development, and effector functions. B cell receptor (BCR)-initiated Ca2+ mobilization is sourced from two pathways: one is the release of Ca2+ from the intracellular stores, endoplasmic reticulum (ER), and other is the prolonged influx of extracellular Ca2+ induced by depleting the stores via store-operated calcium entry (SOCE) and calcium release-activated calcium (CRAC) channels. The identification of stromal interaction molecule 1(STIM1), the ER Ca2+ sensor, and Orai1, a key subunit of the CRAC channel pore, has now provided the tools to understand the mode of Ca2+ influx regulation and physiological relevance. Herein, we discuss our current understanding of the molecular mechanisms underlying BCR-triggered Ca2+ signaling as well as its contribution to the B cell biological processes and diseases.

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Siglec-G Regulates B1 Cell Survival and Selection

Cited by 57 publications

References 35 publications

Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

The Ligand-Binding Domain of Siglec-G Is Crucial for Its Selective Inhibitory Function on B1 Cells

Role of Calcium Signaling in B Cell Activation and Biology

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