Nanoscale organization and dynamics of the siglec <scp>CD</scp>22 cooperate with the cytoskeleton in restraining <scp>BCR</scp> signalling

Gasparrini, Francesca; Feest, Christoph; Bruckbauer, Andreas; Mattila, Pieta K.; Müller, Jennifer; Nitschke, Lars; Bray, Dennis; Batista, Facundo D.

doi:10.15252/embj.201593027

Cited by 96 publications

(132 citation statements)

References 83 publications

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“…An important factor that controls the ability of CD22 to negatively regulate BCR signaling is localization of CD22 to clathrin-coated pits (67). Notably, this membrane localization is driven by interactions with glycan ligands on their cognate receptors, which are neighboring CD22 receptors(68), with the net effect being that CD22 is largely secluded away from the BCR(18, 53, 69). In this aspect, it is satisfying that hCD22 on our transgenic B-cells high degree of colocalization with mCD22, demonstrating the cis glycan ligands on murine B-cells are sufficient to regulate hCD22 localization.…”

Section: Discussionmentioning

confidence: 99%

“…B-cells lacking α2-6-linked sialic acids from ST6Gal1 −/− mice(16) or knock-in mice having a mutant version of CD22 not capable of binding its glycan ligands(5), both have increased association of CD22 with the BCR and, consequently, blunted BCR signaling, demonstrating that interactions between CD22 and cis glycan ligands on the same B-cell keep it sequestered away from the BCR(17). Moreover, a detailed high resolution microscopy study has validated these claims(18). Interestingly, B-cells from CD22 −/− mice do generate a modest degree of hyper-responsiveness to BCR signaling following stimulation with anti-IgM(5, 19–22); this modest increase shows that there may be a small amount of co-localization between CD22 and BCR that occurs in a non-ligand dependent manner in wild-type mice.…”

Section: Introductionmentioning

confidence: 89%

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Human CD22 Inhibits Murine B Cell Receptor Activation in a Human CD22 Transgenic Mouse Model

Bednar

Shanina

Ballet

et al. 2017

The Journal of Immunology

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CD22, a sialic-acid binding immunoglobulin type-lectin (Siglec) family member, is an inhibitory co-receptor of the B-cell receptor (BCR) with established roles in health and disease. The restricted expression pattern of CD22 on B-cells and most B-cell lymphomas has made CD22 a therapeutic target for B-cell-mediated diseases. Models to better understand how in vivo targeting of CD22 translates to human disease are needed. Here, we report development of a transgenic mouse expressing human CD22 (hCD22) in B-cells and assess its ability to functionally substitute for murine CD22 (mCD22) for regulation of BCR signaling, antibody responses, homing, and tolerance. Expression of hCD22 on transgenic murine B-cells is comparable to expression on human primary B-cells, and co-localizes with mCD22 on the cell surface. Murine B-cells expressing only hCD22 have identical calcium (Ca2+) flux responses in response to anti-IgM as mCD22-expressing WT B-cells. Furthermore, hCD22 transgenic mice on a mCD22−/− background have restored levels of marginal zone B-cells and antibody responses compared to deficiencies observed in CD22−/− mice. Consistent with these observations, hCD22 transgenic mice develop normal humoral responses in a peanut allergy oral sensitization model. Homing of B-cells to Peyer’s patches (PP) was partially rescued by expression of hCD22 compared to CD22−/− B-cells, although not to WT levels. Notably, Siglec-engaging antigenic liposomes (STALs) formulated with a hCD22 ligand were shown to prevent B-cell activation, increase cell death, and induce tolerance in vivo. This hCD22 transgenic mouse will be a valuable model for investigating the function of hCD22 and pre-clinical studies targeting hCD22.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Human CD22 Inhibits Murine B Cell Receptor Activation in a Human CD22 Transgenic Mouse Model

Bednar

Shanina

Ballet

et al. 2017

The Journal of Immunology

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“…Single molecule imaging of CD22 indicates that it bounces off actin barriers without being trapped 108 . Such behavior suggests that actin effectively increases CD22 concentration.…”

Section: [H1] Cytoskeletal Regulation Of Bcr Signallingmentioning

confidence: 99%

“…The diffusion of CD22 is primarily regulated by interactions of its lectin domain with cell surface glycoproteins, including PTPRC. Mutation of the lectin binding domain increases CD22 diffusion and improves the negative regulation of BCR signaling [108][109][110] .…”

Section: [H1] Cytoskeletal Regulation Of Bcr Signallingmentioning

confidence: 99%

Cytoskeletal control of B cell responses to antigens

Tolar

2017

Nat Rev Immunol

124

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The actin cytoskeleton is essential for cell mechanics and has increasingly been implicated in the regulation of cell signalling. In B cells, the actin cytoskeleton couples extensively to B cell receptor (BCR) signalling pathways and its defects can either enhance or suppress B cell activation. Recent insights from single-cell imaging and biophysical techniques suggest that actin orchestrates BCR signalling at the plasma membrane through effects on protein diffusion, and that it regulates antigen discrimination through the biomechanics of immune synapses. These mechanical functions also play a role in the adaptation of B cell subsets to specialized tasks during antibody responses.3

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“…Indeed, we recently showed that IgD-only, but not IgM-only, B cells were protected from differentiating into short-lived plasma cells and autoantibody-secreting plasma cells in the absence of Lyn [22]. As CD22 must diffuse rapidly to surveil abundant BCR molecules on the B cell surface, it is possible that CD22 can more easily access IgM clusters, which are less dense than IgD clusters [38,51]. The relative ability of other co-receptors to restrain and enhance IgM and IgD signaling, and the functional consequences thereof, is of great interest and remains largely unexplored.…”

Section: Introductionmentioning

confidence: 99%

Control of autoreactive B cells by IgM and IgD B cell receptors: maintaining a fine balance

Noviski

Zikherman

2018

Current Opinion in Immunology

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A substantial fraction of mature naïve B cells recognize endogenous antigens, and this autoreactivity must be controlled to prevent autoantibody secretion. Selective downregulation of the IgM BCR on autoreactive B cells has long been appreciated, and recent findings illustrate how this might impose tolerance. The BCR isotype maintained on autoreactive B cells, IgD, is less sensitive to endogenous antigens than IgM. This reduced sensitivity may be conferred by structural properties of IgD and/or differential association with activating and inhibitory co-receptors. Once activated, autoreactive B cells are normally excluded from rapid plasma cell responses, but they can enter the germinal center and lose their autoreactivity through a mutation-selection process termed clonal redemption.

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Nanoscale organization and dynamics of the siglec CD22 cooperate with the cytoskeleton in restraining BCR signalling

Cited by 96 publications

References 83 publications

Human CD22 Inhibits Murine B Cell Receptor Activation in a Human CD22 Transgenic Mouse Model

Human CD22 Inhibits Murine B Cell Receptor Activation in a Human CD22 Transgenic Mouse Model

Cytoskeletal control of B cell responses to antigens

Control of autoreactive B cells by IgM and IgD B cell receptors: maintaining a fine balance

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