The Down-Modulation of CD4 Induced by the GM1 Ganglioside Is Regulated by Phosphatases and Kinases: Evidence from Enzyme Inhibitors and Anti-CD45 Antibodies

Krifuks, Oleg; Bergel'son, L. D.; Schlesinger, Michael

doi:10.1006/cimm.1998.1311

Cited by 13 publications

(9 citation statements)

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“…In practice, CD4 modulation is probably redundant as an inhibitory mechanism since others may operate in lieu of, or prior to the occurrence of modulation. The underlying cause of YTS177‐mediated modulation remains unclear but it would be interesting to discern whether it shared the same basis as other agents known to modulate CD4, such as GM1 gangliosides or PMA 23.…”

Section: Discussionmentioning

confidence: 99%

Perturbation of naive TCR transgenic T cell functional responses and upstream activation events by anti-CD4 monoclonal antibodies

et al. 2002

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It is well established that non‐depleting anti‐CD4 monoclonal antibodies (mAb) have potent immunomodulatory properties in vivo and as such can induce a profound state of tolerance. Receptor blockade, CD4 modulation, or the transmission of a negative signal have all been proposed to explain their effects, however their precise mechanism of action, particularly at the level of cellular signaling, remains obscure. Experiments were thus carried out to examine the underlying mechanisms of action of two non‐depleting anti‐mouse CD4 mAb, YTS177 and KT6, which differ in their ability to modulate CD4 expression. The effects of the mAb were examined on CD4+ T cells derived from D0.11.10 TCR transgenic mice. Functional studies revealed that both mAb could effectively block antigen‐driven proliferation and IL‐2 production but had only modest effects at higher peptide doses. Importantly, mAb pre‐treatment of T cells stimulated by sub‐optimal peptide seemed to induce an anergy‐like state making them unresponsive to subsequent re‐stimulation. Analysis of intracellular signaling demonstrated that certain key upstream events such as the phosphorylation of Zap‐70 and LAT were also blocked by mAb pretreatment which may be due to interference with stable T cell‐APC conjugate formation.

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Section: Discussionmentioning

confidence: 99%

Perturbation of naive TCR transgenic T cell functional responses and upstream activation events by anti-CD4 monoclonal antibodies

et al. 2002

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“…For example, gangliosides have been established as receptors for platelet-derived growth factor, epidermal growth factor, and insulin [26,27]. Other gangliosides have immunosuppressive effects on T cells, B cells, and macrophages [23,[28][29][30][31]. Immunomodulatory responses in those immunocompetent cells are likely induced by signals which are translated across the membrane after binding of ligands to gangliosides [26,[32][33][34][35].…”

Section: Gangliosidesmentioning

confidence: 99%

Cholera toxin, LT-I, LT-IIa and LT-IIb: the critical role of ganglioside binding in immunomodulation by Type I and Type II heat-labile enterotoxins

Connell

2007

Expert Review of Vaccines

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The heat-labile enterotoxins (HLT) expressed by Vibrio cholerae (cholera toxin) and Escherichia coli (LT-I, LT-IIa, and LT-IIb) are potent systemic and mucosal adjuvants. Co-administration of the enterotoxins with a foreign antigen (Ag) produces an augmented immune response to that antigen. Although each enterotoxin has potent adjuvant properties, the means by which the enterotoxins induce various immune responses are distinctive for each adjuvant. Various mutants have been engineered to dissect the functions of the enterotoxins required for their adjuvanticity. The capacity to strongly bind to one or more specific ganglioside receptors appears to drive the distinctive immunomodulatory properties associated with each enterotoxin. Mutant enterotoxins with ablated or altered ganglioside binding affinities have been employed to investigate the role of gangliosides in enterotoxin-dependent immunomodulation.

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“…Gangliosides are believed to be involved in cell−cell/substratum interactions (), modulation of transmembrane signaling ( − ), alteration of membrane fluidity ( , ), calcium homeostasis, and synaptic transmission ( , ). Many studies ascertained the capability of gangliosides to affect membrane protein activity ( − ). Cation fluxes through Na + and Ca 2+ plasma membrane channels appear to be modulated by gangliosides, particularly GM 1 ( , ).…”

mentioning

confidence: 99%

“…Cation fluxes through Na + and Ca 2+ plasma membrane channels appear to be modulated by gangliosides, particularly GM 1 ( , ). Garcia and Miller () and Krifuks et al () showed that GM 1 preferentially elicited the down-modulation of CD 4 , the binding site of HIV (the aetiologic agent of AIDS), on the surface of T-lymphocytes ( , ). Gangliosides are also implicated in receptor function; e.g., GM 1 acts as the receptor of the cholera toxin ( , ) and is essential to the penetration of the toxin into the cell membrane ().…”

mentioning

confidence: 99%

“…Cation fluxes through Na + and Ca 2+ plasma membrane channels appear to be modulated by gangliosides, particularly GM 1 (18,19). Garcia and Miller (14) and Krifuks et al (15) FIGURE 1: Chemical structures of the four major gangliosides (GM 1 , GD 1a , GD 1b , and GT 1b ) of mammalian brain, with the nomenclature of Svennerholm (1963). The gangliosides have a ceramide backbone and a common neutral tetrasaccharide portion (galactosyl β1f3 N-acetylgalactosaminyl β1f4 galactosyl β1f4 glucosyl) to which are bound sialic acid residues (structure in the dashed box with R 2 ) H).…”

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confidence: 99%

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FTIR Study of the Monosialoganglioside GM₁ in Perdeuterated Dimyristoylglycerophosphocholine (DMPC_d54) Multilamellar Bilayers: Spectroscopic Evidence of a Significant Interaction between Ca²⁺ Ions and the Sialic Acid Moiety of GM₁

Kates

Carrier

2000

Biochemistry

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Fourier transform infrared (FTIR) spectroscopy was employed to study bovine brain GM1 and perdeuterated dimyristoylglycerophosphocholine (DMPCd54) multilamellar dispersions (mole fractions of GM1 in DMPCd54: 0.12, 0.15, 0.19, 0.26, 0.34, 0.41, and 0.58), in the absence and presence of 10 mM CaCl2. GM1 micelles did not display a thermal phase transition in the temperature range 5-60 degrees C. Moreover, the ceramide moiety of GM1 inserted into the hydrophobic core of DMPCd54 bilayers and was capable of undergoing a single, cooperative phase transition (Tm = 22-28 degrees C, depending on GM1 content) in a bilayer system. This suggested that the mixed bilayers consisted of a homogeneous mixture and that GM1 was uniformly dispersed in the bilayer plane rather than segregated into regions of relative enrichment. The coexistence of GM1 and DMPCd54 in a bilayer environment induced a rearrangement of the interfacial hydrogen bonding network of the amide I and ester C=O groups, relative to GM1 micelles and DMPCd54 bilayers, respectively. The modifications induced by GM1 might ultimately modulate surface events such as lipid-lipid and/or lipid-protein interactions. The spectroscopic results also suggested that the glycolipid's headgroup surface location and conformation in bilayers allow GM1 to act as a receptor for Ca2+ via its sialic acid moiety.

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The Down-Modulation of CD4 Induced by the GM1 Ganglioside Is Regulated by Phosphatases and Kinases: Evidence from Enzyme Inhibitors and Anti-CD45 Antibodies

Cited by 13 publications

References 34 publications

Perturbation of naive TCR transgenic T cell functional responses and upstream activation events by anti-CD4 monoclonal antibodies

Perturbation of naive TCR transgenic T cell functional responses and upstream activation events by anti-CD4 monoclonal antibodies

Cholera toxin, LT-I, LT-IIa and LT-IIb: the critical role of ganglioside binding in immunomodulation by Type I and Type II heat-labile enterotoxins

FTIR Study of the Monosialoganglioside GM₁ in Perdeuterated Dimyristoylglycerophosphocholine (DMPC_d54) Multilamellar Bilayers: Spectroscopic Evidence of a Significant Interaction between Ca²⁺ Ions and the Sialic Acid Moiety of GM₁

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The Down-Modulation of CD4 Induced by the GM1 Ganglioside Is Regulated by Phosphatases and Kinases: Evidence from Enzyme Inhibitors and Anti-CD45 Antibodies

Cited by 13 publications

References 34 publications

Perturbation of naive TCR transgenic T cell functional responses and upstream activation events by anti-CD4 monoclonal antibodies

Perturbation of naive TCR transgenic T cell functional responses and upstream activation events by anti-CD4 monoclonal antibodies

Cholera toxin, LT-I, LT-IIa and LT-IIb: the critical role of ganglioside binding in immunomodulation by Type I and Type II heat-labile enterotoxins

FTIR Study of the Monosialoganglioside GM1 in Perdeuterated Dimyristoylglycerophosphocholine (DMPCd54) Multilamellar Bilayers: Spectroscopic Evidence of a Significant Interaction between Ca2+ Ions and the Sialic Acid Moiety of GM1

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FTIR Study of the Monosialoganglioside GM₁ in Perdeuterated Dimyristoylglycerophosphocholine (DMPC_d54) Multilamellar Bilayers: Spectroscopic Evidence of a Significant Interaction between Ca²⁺ Ions and the Sialic Acid Moiety of GM₁