Siglec-G is a B1 cell–inhibitory receptor that controls expansion and calcium signaling of the B1 cell population

Hoffmann, Anja; Kerr, Sheena C.; Jellusova, Julia; Zhang, Jiquan; Weisel, Florian; Wellmann, Ute; Winkler, Thomas; Kneitz, Burkhard; Crocker, Paul R.; Nitschke, Lars

doi:10.1038/ni1480

Cited by 171 publications

(260 citation statements)

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“…Conversely, a complex B-cell phenotype characterized by reduced numbers of follicular B cells, elevated numbers of B-1 B cells and to some extent MZ B cells, B-cell hyper-responsiveness and auto-antibody formation is found in genetic changes that increase BCR signaling. These include gain-of-function mutants of Lyn or Plcg2, deficiency for PTEN, a lipid phosphatase that antagonizes PI3K activity, overexpression of CD19 or mutations that disable inhibitory signaling of membrane receptors such as CD22, Pir-B, Siglec-G and FcgRIIB or their downstream signaling molecules Shp1 or Ship [12][13][14][15][16][17][18][19][20][21].Btk is a member of the Tec protein tyrosine kinase family that mediates many aspects of B-cell development, survival and function [8,22]. Whereas in humans Btk mutations cause a severe arrest of B-cell development at the pre-B-cell stage leading to X-linked agammaglobulinemia, in the mouse there is only a mild pre-B-cell defect, differentiation of transitional into mature peripheral B cells is impaired and B-1 cells are lacking [23][24][25].…”

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Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

et al. 2010

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B-cell receptor (BCR)-mediated signals provide the basis for B-cell differentiation in the BM and subsequently into follicular, marginal zone, or B-1 B-cell subsets. We have previously shown that B-cell-specific expression of the constitutive active E41K mutant of the BCR-associated molecule Bruton's tyrosine kinase (Btk) leads to an almost complete deletion of immature B cells in the BM. Here, we report that low-level expression of the E41K or E41K-Y223F Btk mutants was associated with reduced follicular B-cell numbers and significantly increased proportions of B-1 cells in the spleen. Crosses with 3-83md and VH81X BCR Tg mice showed that constitutive active Btk expression did not change follicular, marginal zone, or B-1 B-cell fate choice, but resulted in selective expansion or survival of B-1 cells. Residual B cells were hyperresponsive and manifested sustained Ca 21 mobilization. They were spontaneously driven into germinal center-independent plasma cell differentiation, as evidenced by increased numbers of IgM 1 plasma cells in spleen and BM and significantly elevated serum IgM. Because anti-nucleosome autoantibodies and glomerular IgM deposition were present, we conclude that constitutive Btk activation causes defective B-cell tolerance, emphasizing that Btk signals are essential for appropriate regulation of B-cell activation. IntroductionSignals transmitted by the B-cell receptor (BCR) control the antigen response of B cells and are also essential regulators of survival, tolerance and differentiation (reviewed in [1,2]). Inducible and stage-specific targeting experiments demonstrated that mature B cells undergo apoptosis upon in vivo BCR ablation or mutation of one of its signaling units, Ig-a, and consequently disappear from the circulation [3,4]. A critical survival signal is provided by PI3K [5], but how this signaling is initiated in resting mature B cells is not fully understood. BCR signal strength is also a key factor in deciding between the three functionally distinct mature B-cell compartments of follicular, marginal zone (MZ) and B-1 B cells. Increases in BCR signaling strength, induced by low-dose selfantigen, direct maturation of naive immature B cells from the follicular into the B-1 or MZ B-cell fate [6,7]. Eur. J. Immunol. 2010. 40: 2643-2654 DOI 10.1002 Leukocyte signaling 2643In mature B cells, BCR engagement induces phosphorylation of Ig-a and Ig-b and the formation of a lipid raft-associated calcium-signaling module. In this complex Syk phosphorylates the adapter molecule Slp65, thereby providing docking sites for Bruton's tyrosine kinase (Btk) and phospholipase Cg2 (Plcg2). Activation of Plcg2 by Btk results in the generation of the Ca 21 -releasing factors inositol-1,4,5-trisphosphate and diacylglycerol (reviewed in [8,9]). During these events various co-receptors modulate BCR signaling either positively or negatively [10].Deficiencies of BCR signaling molecules, such as Btk, Slp65 or Plcg2 or the excitatory co-receptor CD19 result in a hyporesponsive phenotype, mainly characterize...

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Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

et al. 2010

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“…Because we found increased proliferation in the spleen and decreased apoptosis of B1 cells of Dkk3 2/2 mice, we conclude that DKK3 limits the self-maintenance capacity of B1 cells. SiglecG has been shown to control the expansion of the B1 cell population (31). Therefore, the decreased expression of SiglecG in Dkk3 2/2 mice might contribute to the increase in B1 cell numbers.…”

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confidence: 99%

“…SiglecG is expressed highly on B1 cells and was shown to be a regulatory protein controlling calcium signaling and inhibiting the expansion of the B1 cell population (31). To confirm that SiglecG is downregulated also on the protein level in B cells of Dkk3 2/2 mice, B1 and B2 cells were analyzed by FACS for the expression of this molecule.…”

Section: Dkk3 May Contribute To the Control Of Bcr Signalingmentioning

confidence: 99%

“…Single-cell suspensions of BM, spleen, lymph nodes, or peritoneal cavity lavage were incubated 15 min at 4˚C with anti-CD16/CD32 Fc-receptor block and washed, followed by 30 min at 4˚C incubation with varying combinations of the following Abs: anti-CD19 (BioLegend), anti-B220 (BD Biosciences), anti-CD5 (BD Biosciences), anti-CD43 (BD Biosciences), anti-CD23 (BioLegend), anti-CD3 (BD Biosciences), anti-l (BD Biosciences), anti-k (BD Biosciences), anti-CD93 (BioLegend), anti-CD25 (BD Biosciences), anti-c-kit (BD Biosciences), anti-CD21/35 (BD Biosciences), anti-IL-10 (BD Biosciences), and anti-SiglecG-biotin (31). Staining was performed in Dulbecco's PBS (dPBS) containing 2% FCS and 0.1% sodium azide.…”

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Dickkopf-3 Acts as a Modulator of B Cell Fate and Function

Ludwig

Federico

Prokosch

et al. 2015

The Journal of Immunology

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The mechanisms responsible for the generation of a mature B1 and B2 cell compartment are still poorly understood. In this study, we demonstrated that absence of Dickkopf-3 (DKK3) led to changes in the composition of the B cell compartment, which were due to an altered development and maintenance program of B cells. Development of B2 cells was impaired at the pre- and immature B cell stage, resulting in decreased numbers of follicular B cells in adult DKK3-deficient mice. Furthermore, DKK3 limited B1 cell self-maintenance in the periphery, by decreasing the survival and proliferation behavior of B1 cells. DKK3 may act via the BCR signaling pathway, as Ca2+ influx upon BCR stimulation was increased and SiglecG, a molecule shown to inhibit Calcium signaling, was downregulated in the absence of DKK3. DKK3-deficient mice exhibited altered Ab responses and an increased secretion of the cytokine IL-10. Additionally, DKK3 limited autoimmunity in a model of systemic lupus erythematosus. In summary, we identified DKK3 as a novel modulator interfering with B cell fate as well as the maintenance program of B cells, leading to changes in B cell immune responses.

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Siglec‐G Suppresses CD8⁺ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy

Yin,

Li,

Shen

et al. 2024

Advanced Science

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CD8+ T cells play a critical role in cancer immune‐surveillance and pathogen elimination. However, their effector function can be severely impaired by inhibitory receptors such as programmed death‐1 (PD‐1) and T cell immunoglobulin domain and mucin domain‐3 (Tim‐3). Here Siglec‐G is identified as a coinhibitory receptor that limits CD8+ T cell function. Siglec‐G is highly expressed on tumor‐infiltrating T cells and is enriched in the exhausted T cell subset. Ablation of Siglec‐G enhances the efficacy of adoptively transferred T cells and chimeric antigen receptor (CAR) T cells in suppressing solid tumors growth. Mechanistically, sialoglycan ligands, such as CD24 on tumor cells, activate the Siglec‐G‐SHP2 axis in CD8+ T cells, impairing metabolic reprogramming from oxidative phosphorylation to glycolysis, which dampens cytotoxic T lymphocyte (CTL) activation, expansion, and cytotoxicity. These findings discover a critical role for Siglec‐G in inhibiting CD8+ T cell responses, suggesting its potential therapeutic effect in adoptive T cell therapy and tumor immunotherapy.

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Siglec-G is a B1 cell–inhibitory receptor that controls expansion and calcium signaling of the B1 cell population

Cited by 171 publications

References 48 publications

Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

Dickkopf-3 Acts as a Modulator of B Cell Fate and Function

Siglec‐G Suppresses CD8⁺ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy

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Siglec-G is a B1 cell–inhibitory receptor that controls expansion and calcium signaling of the B1 cell population

Cited by 171 publications

References 48 publications

Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

Dickkopf-3 Acts as a Modulator of B Cell Fate and Function

Siglec‐G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy

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Siglec‐G Suppresses CD8⁺ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy