Dendritic Cell Maturation Results in Pronounced Changes in Glycan Expression Affecting Recognition by Siglecs and Galectins

Bax, Marieke; García-Vallejo, Juan J.; Jang-Lee, Jihye; North, Simon J.; Gilmartin, Tim; Hernandez, Gilberto E.; Crocker, Paul R.; Leffler, Hakon; Head, Steven R.; Haslam, Stuart M.; Dell, Anne; Kooyk, Yvette van

doi:10.4049/jimmunol.179.12.8216

Cited by 108 publications

(102 citation statements)

References 75 publications

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“…Specifically, those antigens displaying no CD22 ligands were potent activators, those with modest levels of CD22 ligand substitution were weak activators, and those with high levels were extremely effective suppressors. These findings are consistent with observations that tolerogenic or immature cells display ␣2-6 sialic acid moieties at higher levels than immunogenic or activated cells (49). Moreover, our results indicate that changes in carbohydrate expression and recognition can have dramatic effects on immune reactivity and tolerance.…”

Section: Discussionsupporting

confidence: 92%

Sialylated multivalent antigens engage CD22in transand inhibit B cell activation

Courtney¹,

Puffer²,

Pontrello

et al. 2009

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

118

178

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CD22 is an inhibitory coreceptor on the surface of B cells that attenuates B cell antigen receptor (BCR) signaling and, therefore, B cell activation. Elucidating the molecular mechanisms underlying the inhibitory activity of CD22 is complicated by the ubiquity of CD22 ligands. Although antigens can display CD22 ligands, the receptor is known to bind to sialylated glycoproteins on the cell surface. The propinquity of CD22 and cell-surface glycoprotein ligands has led to the conclusion that the inhibitory properties of the receptor are due to cis interactions. Here, we examine the functional consequences of trans interactions by employing sialylated multivalent antigens that can engage both CD22 and the BCR. Exposure of B cells to sialylated antigens results in the inhibition of key steps in BCR signaling. These results reveal that antigens bearing CD22 ligands are powerful suppressors of B cell activation. The ability of sialylated antigens to inhibit BCR signaling through trans CD22 interactions reveals a previously unrecognized role for the Siglec-family of receptors as modulators of immune signaling.B cell antigen receptor ͉ multivalency ͉ sialic acid ͉ siglec ͉ autoimmunity T he initiation of an immune response or the prevention of autoimmunity depends upon the ability of the B cell antigen receptor (BCR) to transmit signals that positively or negatively regulate B lymphocyte survival, proliferation, and differentiation (1). To avoid detrimental autoimmune responses, a means of differentiating between foreign and self-antigens is required; coreceptors that modulate BCR signaling can ensure that these distinctions are made. CD22 is an inhibitory coreceptor that can attenuate BCR signaling (2, 3). CD22 null mice possess hyperresponsive B cells (4), illustrating a role for CD22 in establishing a threshold for B cell activation. Specifically, an increase in intracellular Ca 2ϩ ion concentration is a hallmark of B cell activation (5, 6), and B cells isolated from CD22 null mice display increased Ca 2ϩ flux in response to antigen (4, 7). Thus, loss of CD22 results in a lowering of the threshold for B cell activation. Other data also support this conclusion: CD22 null mice exhibit increased serum IgM concentrations, decreased surface IgM levels on peripheral B cells, increased induction of apoptosis in response to BCR crosslinking, and increased serum autoantibody titers (8). These observations are consistent with the loss of CD22 leading to increased sensitivity and chronic B cell activation.The process of B cell activation ensues upon binding of multivalent antigen to the BCR. Antigen-induced clustering elicits phosphorylation of the cytoplasmic immunoreceptor tyrosinebased activation motifs (ITAMs), which are present in the BCRassociated signaling proteins Ig␣/␤. The phosphorylation reaction is catalyzed by Src-family kinases such as Lyn. Upon phosphorylation of the BCR components, Syk kinase is recruited to the BCR signaling complex (9). Syk is essential for propagating BCR signaling (10, 11). It acts along with...

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Section: Discussionsupporting

confidence: 92%

Sialylated multivalent antigens engage CD22in transand inhibit B cell activation

Courtney¹,

Puffer²,

Pontrello

et al. 2009

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

118

178

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“…Analysis of gene expression was conducted using a custom gene microarray (GLYCOv2 chip) produced by Affymetrix for the Consortium for Functional Glycomics (http://www.functionalglycomics.org) (42). Hybridization and scanning of the chip were performed according to the recommended protocols (43).…”

Section: Methodsmentioning

confidence: 99%

Regulated and aberrant glycosylation modulate cardiac electrical signaling

Montpetit

Stocker

Schwetz

et al. 2009

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

Self Cite

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Millions afflicted with Chagas disease and other disorders of aberrant glycosylation suffer symptoms consistent with altered electrical signaling such as arrhythmias, decreased neuronal conduction velocity, and hyporeflexia. Cardiac, neuronal, and muscle electrical signaling is controlled and modulated by changes in voltage-gated ion channel activity that occur through physiological and pathological processes such as development, epilepsy, and cardiomyopathy. Glycans attached to ion channels alter channel activity through isoform-specific mechanisms. Here we show that regulated and aberrant glycosylation modulate cardiac ion channel activity and electrical signaling through a cell-specific mechanism. Data show that nearly half of 239 glycosylation-associated genes (glycogenes) were significantly differentially expressed among neonatal and adult atrial and ventricular myocytes. The N-glycan structures produced among cardiomyocyte types were markedly variable. Thus, the cardiac glycome, defined as the complete set of glycan structures produced in the heart, is remodeled. One glycogene, ST8sia2, a polysialyltransferase, is expressed only in the neonatal atrium. Cardiomyocyte electrical signaling was compared in control and ST8sia2 (؊/؊) neonatal atrial and ventricular myocytes. Action potential waveforms and gating of less sialylated voltage-gated Na ؉ channels were altered consistently in ST8sia2 (؊/؊) atrial myocytes. ST8sia2 expression had no effect on ventricular myocyte excitability. Thus, the regulated (between atrium and ventricle) and aberrant (knockout in the neonatal atrium) expression of a single glycogene was sufficient to modulate cardiomyocyte excitability. A mechanism is described by which cardiac function is controlled and modulated through physiological and pathological processes that involve regulated and aberrant glycosylation. action potentials ͉ cardiomyocyte ͉ glycomics ͉ ion channels ͉ sialic acids

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“…Furthermore, a-1,2-mannosidase I and a-mannosidase II were reported to be downregulated in mature human monocyte-derived DCs (6,10), whereas Man1a mRNA was only transiently decreased upon maturation of murine CD11c + DCs isolated from spleen (12). These findings hint at a maturation-dependent role for a-1,2-mannosidase I-processed N-glycans.…”

mentioning

confidence: 89%

“…Recently, a genetic remodeling of glycosylation upon DC maturation was demonstrated by glyco-gene microarray expression analysis (6,7) and by quantitative RT-PCR (8,9). A number of transcripts for enzymes involved in N-glycan synthesis was found to be increased during DC differentiation but downregulated after their maturation (6-8, 10, 11).…”

mentioning

confidence: 99%

Control of TNF-Induced Dendritic Cell Maturation by Hybrid-Type N-Glycans

Schlickeiser

Stanojlović²,

Appelt

et al. 2011

The Journal of Immunology

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The activity of α-1,2-mannosidase I is required for the conversion of high-mannose to hybrid-type (ConA reactive) and complex-type N-glycans (Phaseolus vulgaris-leukoagglutinin [PHA-L] reactive) during posttranslational protein N-glycosylation. We recently demonstrated that α-1,2-mannosidase I mRNA decreases in graft-infiltrating CD11c+ dendritic cells (DCs) prior to allograft rejection. Although highly expressed in immature DCs, little is known about its role in DC functions. In this study, analysis of surface complex-type N-glycan expression by lectin staining revealed the existence of PHA-Llow and PHA-Lhigh subpopulations in murine splenic conventional DCs, as well as in bone marrow-derived DC (BMDCs), whereas plasmacytoid DCs are nearly exclusively PHA-Lhigh. Interestingly, all PHA-Lhigh DCs displayed a strongly reduced responsiveness to TNF-α–induced p38-MAPK activation compared with PHA-Llow DCs, indicating differences in PHA-L–binding capacities between DCs with different inflammatory properties. However, p38 phosphorylation levels were increased in BMDCs overexpressing α-1,2-mannosidase I mRNA. Moreover, hybrid-type, but not complex-type, N-glycans are required for TNF-α–induced p38-MAPK activation and subsequent phenotypic maturation of BMDCs (MHC-II, CD86, CCR7 upregulation). α-1,2-mannosidase I inhibitor-treated DCs displayed diminished transendothelial migration in response to CCL19, homing to regional lymph nodes, and priming of IFN-γ–producing T cells in vivo. In contrast, the activity of α-1,2-mannosidase I is dispensable for LPS-induced signaling, as well as the DCs’ general capability for phenotypic and functional maturation. Systemic application of an α-1,2-mannosidase I inhibitor was able to significantly prolong allograft survival in a murine high-responder corneal transplantation model, further highlighting the importance of N-glycan processing by α-1,2-mannosidase I for alloantigen presentation and T cell priming.

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Dendritic Cell Maturation Results in Pronounced Changes in Glycan Expression Affecting Recognition by Siglecs and Galectins

Cited by 108 publications

References 75 publications

Sialylated multivalent antigens engage CD22in transand inhibit B cell activation

Sialylated multivalent antigens engage CD22in transand inhibit B cell activation

Regulated and aberrant glycosylation modulate cardiac electrical signaling

Control of TNF-Induced Dendritic Cell Maturation by Hybrid-Type N-Glycans

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