Galectin-9 regulates the threshold of B cell activation and autoimmunity

Smith, Logan K.; Fawaz, Kareem; Treanor, Bebhinn

doi:10.7554/elife.64557

Cited by 16 publications

(5 citation statements)

References 42 publications

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“…Our previous works demonstrated that CB-SCs displayed PD-L1 (CD274) [32] and herpesvirus entry mediator (HVEM, CD270) [5], which contributed to the immune modulations of CB-SCs on T cells. To reveal the molecular mechanisms underlying the immune modulation of CB-SCs on B cells, we further explored other potential surface molecules such as galectins [28,33], which are involved in the immune suppression of human mesenchymal stem cells (MSC) on both T and B cells [26,34]. Galectins have been recognized as essential regulators contributing to the induction of an immune tolerance and homeostasis, therefore functioning as attractive therapeutic targets for attenuating autoimmune and inflammation disorders [23,35].…”

Section: The Expression Of Gal-9 On Cb-scs Acts As a Key Molecule Con...mentioning

confidence: 99%

Suppression of B-Cell Activation by Human Cord Blood-Derived Stem Cells (CB-SCs) through the Galectin-9-Dependent Mechanism

Hu,

Song,

et al. 2024

IJMS

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Background: We developed the Stem Cell Educator therapy among multiple clinical trials based on the immune modulations of multipotent cord blood-derived stem cells (CB-SCs) on different compartments of immune cells, such as T cells and monocytes/macrophages, in type 1 diabetes and other autoimmune diseases. However, the effects of CB-SCs on the B cells remained unclear. To better understand the molecular mechanisms underlying the immune education of CB-SCs, we explored the modulations of CB-SCs on human B cells. Methods: CB-SCs were isolated from human cord blood units and confirmed by flow cytometry with different markers for their purity. B cells were purified by using anti-CD19 immunomagnetic beads from human peripheral blood mononuclear cells (PBMCs). Next, the activated B cells were treated in the presence or absence of coculture with CB-SCs for 7 days before undergoing flow cytometry analysis of phenotypic changes with different markers. Reverse transcription-polymerase chain reaction (RT-PCR) was utilized to evaluate the levels of galectin expressions on CB-SCs with or without treatment of activated B cells in order to find the key galectin that was contributing to the B-cell modulation. Results: Flow cytometry demonstrated that the proliferation of activated B cells was markedly suppressed in the presence of CB-SCs, leading to the downregulation of immunoglobulin production from the activated B cells. Phenotypic analysis revealed that treatment with CB-SCs increased the percentage of IgD+CD27− naïve B cells, but decreased the percentage of IgD−CD27+ switched B cells. The transwell assay showed that the immune suppression of CB-SCs on B cells was dependent on the galectin-9 molecule, as confirmed by the blocking experiment with the anti-galectin-9 monoclonal antibody. Mechanistic studies demonstrated that both calcium levels of cytoplasm and mitochondria were downregulated after the treatment with CB-SCs, causing the decline in mitochondrial membrane potential in the activated B cells. Western blot exhibited that the levels of phosphorylated Akt and Erk1/2 signaling proteins in the activated B cells were also markedly reduced in the presence of CB-SCs. Conclusions: CB-SCs displayed multiple immune modulations on B cells through the galectin-9-mediated mechanism and calcium flux/Akt/Erk1/2 signaling pathways. The data advance our current understanding of the molecular mechanisms underlying the Stem Cell Educator therapy to treat autoimmune diseases in clinics.

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Section: The Expression Of Gal-9 On Cb-scs Acts As a Key Molecule Con...mentioning

confidence: 99%

Suppression of B-Cell Activation by Human Cord Blood-Derived Stem Cells (CB-SCs) through the Galectin-9-Dependent Mechanism

Hu,

Song,

et al. 2024

IJMS

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“…This can suppress B cell receptor (BCR) signalling through CD45-mediated recruitment of SHP1 (refs. 55 , 56 ), resulting in an inhibition of B cell activation and their subsequent differentiation into plasma cells 57 . Likewise, changes in the glycosylation of surface proteins of B cells can impact the binding of extracellular galectin-1 and galectin-8 and affect B cell differentiation.…”

Section: Regulation Of Adaptive Immunitymentioning

confidence: 99%

The role of galectins in immunity and infection

Liu

Stowell

2023

Nat Rev Immunol

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The galectin family consists of carbohydrate (glycan) binding proteins that are expressed by a wide variety of cells and bind to galactose-containing glycans. Galectins can be located in the nucleus or the cytoplasm, or can be secreted into the extracellular space. They can modulate innate and adaptive immune cells by binding to glycans on the surface of immune cells or intracellularly via carbohydrate-dependent or carbohydrate-independent interactions. Galectins expressed by immune cells can also participate in host responses to infection by directly binding to microorganisms or by modulating antimicrobial functions such as autophagy. Here we explore the diverse ways in which galectins have been shown to impact immunity and discuss the opportunities and challenges in the field.

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“…The regulatory power of GBPs is not limited to T cells, having also a key role in B-cell development and maturation in which stromal cell derived-galectin-1 may serve as a ligand for pre-BCR signaling [ 46 ]. In this regard, recent evidence highlights the critical role of galectin-9 in setting the threshold of B-cell activation, by regulating the interactions between the BCR and Toll-like receptors (TLRs); loss of this regulatory network was associated with development of autoimmunity [ 47 ]. Similar to T cells, GnT-V-mediated N -glycan branching has also been shown to promote positive selection of B cells by increasing pre-BCR/BCR signaling via CD19 surface retention.…”

Section: Introductionmentioning

confidence: 99%

Immune regulatory networks coordinated by glycans and glycan-binding proteins in autoimmunity and infection

et al. 2023

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The immune system is coordinated by an intricate network of stimulatory and inhibitory circuits that regulate host responses against endogenous and exogenous insults. Disruption of these safeguard and homeostatic mechanisms can lead to unpredictable inflammatory and autoimmune responses, whereas deficiency of immune stimulatory pathways may orchestrate immunosuppressive programs that contribute to perpetuate chronic infections, but also influence cancer development and progression. Glycans have emerged as essential components of homeostatic circuits, acting as fine-tuners of immunological responses and potential molecular targets for manipulation of immune tolerance and activation in a wide range of pathologic settings. Cell surface glycans, present in cells, tissues and the extracellular matrix, have been proposed to serve as “self-associated molecular patterns” that store structurally relevant biological data. The responsibility of deciphering this information relies on different families of glycan-binding proteins (including galectins, siglecs and C-type lectins) which, upon recognition of specific carbohydrate structures, can recalibrate the magnitude, nature and fate of immune responses. This process is tightly regulated by the diversity of glycan structures and the establishment of multivalent interactions on cell surface receptors and the extracellular matrix. Here we review the spatiotemporal regulation of selected glycan-modifying processes including mannosylation, complex N-glycan branching, core 2 O-glycan elongation, LacNAc extension, as well as terminal sialylation and fucosylation. Moreover, we illustrate examples that highlight the contribution of these processes to the control of immune responses and their integration with canonical tolerogenic pathways. Finally, we discuss the power of glycans and glycan-binding proteins as a source of immunomodulatory signals that could be leveraged for the treatment of autoimmune inflammation and chronic infection.

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Galectin-9 regulates the threshold of B cell activation and autoimmunity

Cited by 16 publications

References 42 publications

Suppression of B-Cell Activation by Human Cord Blood-Derived Stem Cells (CB-SCs) through the Galectin-9-Dependent Mechanism

Suppression of B-Cell Activation by Human Cord Blood-Derived Stem Cells (CB-SCs) through the Galectin-9-Dependent Mechanism

The role of galectins in immunity and infection

Immune regulatory networks coordinated by glycans and glycan-binding proteins in autoimmunity and infection

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