Immobilization of glycosylphosphatidylinositol-anchored proteins inhibits T cell growth but not function

Marmor, Mina D.; Bachmann, Martin F.; Ohashi, Pamela S.; Malek, Thomas R.; Julius, Michael

doi:10.1093/intimm/11.9.1381

Cited by 27 publications

(30 citation statements)

References 58 publications

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“…Another line of thoughts is provided by studies dealing with the Ab-mediated recruitment of GPI-anchored proteins on T cells. Such studies have revealed profound similarities between all these molecules, and notably their capacity, following Ab-mediated mobilization, to inhibit clonal T cell expansion through the IL-2R pathway, while preserving the functions of the lymphocytes (48,49). An important issue will be to find out whether PrPC follows the signaling pathway common to most GPI-anchored proteins on T cells, a pathway that results in clonal size control, while leaving intact effector functions such as cytotoxicity or lymphokine production, or whether PrPC initiates its own specific signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Functional Implication of Cellular Prion Protein in Antigen-Driven Interactions between T Cells and Dendritic Cells

Ballerini

Gourdain

Bachy

et al. 2006

The Journal of Immunology

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The cellular prion protein (PrPC) is a host-encoded, GPI-anchored cell surface protein, expressed on a wide range of tissues including neuronal and lymphoreticular cells. PrPC may undergo posttranslational conversion, giving rise to scrapie PrP, the pathogenic conformer considered as responsible for prion diseases. Despite intensive studies, the normal function of PrPC is still enigmatic. Starting from microscope observations showing an accumulation of PrPC at the sites of contact between T cells and Ag-loaded dendritic cells (DC), we have studied the contribution of PrPC in alloantigen and peptide-MHC-driven T/DC interactions. Whereas the absence of PrPC on the DC results in a reduced allogeneic T cell response, its absence on the T cell partner has no apparent effect upon this response. Therefore, PrPC seems to fulfill different functions on the two cell partners forming the synapse. In contrast, PrPC mobilization by Ab reduces the stimulatory properties of DC and the proliferative potential of responding T cells. The contrasted consequences, regarding T cell function, between PrPC deletion and PrPC coating by Abs, suggests that the prion protein acts as a signaling molecule on T cells. Furthermore, our results show that the absence of PrPC has consequences in vivo also, upon the ability of APCs to stimulate proliferative T cell responses. Thus, independent of neurological considerations, some of the evolutionary constraints that may have contributed to the conservation of the Prnp gene in mammalians, could be of immunological origin.

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Section: Discussionmentioning

confidence: 99%

Functional Implication of Cellular Prion Protein in Antigen-Driven Interactions between T Cells and Dendritic Cells

Ballerini

Gourdain

Bachy

et al. 2006

The Journal of Immunology

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“…Clustering of GPI-anchored proteins by mAbs to CD48, CD55, CD59, and CD73, Thy-1, Ly-6, and sgp-60 readily affects T cell activity usually by the induction of T cell proliferation or IL-2 production (9,(43)(44)(45)(46). In contrast, under some experimental conditions mAb binding to GPI-anchored proteins led to inhibition (46 -48) or to a modulation of T cell activation (49). Moreover, T cells lacking GPI-anchored proteins, including GPI-deficient T cells derived from patients with paroxysmal nocturnal hemoglobinuria (50,51) and T cells derived from CD48…”

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of T Cell Activation Via CD147 Through Novel Modulation of Lipid Rafts

Staffler

Szekeres

Schütz

et al. 2003

The Journal of Immunology

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The plasma membrane is compartmentalized into microdomains and the association/dissociation of receptors and signaling molecules with/from these membrane domains is a major principle for regulation of signal transduction. By following the reorganization of microdomains on living cells and performing biochemical studies, we show that Ab targeting of the T cell activation-associated Ag CD147 prevents TCR stimulation-dependent reorganization and clustering of microdomains. Triggering CD147 induces a displacement of the GPI-anchored coreceptors CD48 and CD59 from microdomains in human T lymphocytes. This perturbation of microdomains is accompanied by a selective inhibition of TCR-mediated T cell proliferation. The CD147-inhibited cells secret normal levels of IL-2 but acquire reduced amounts of the IL-2 receptor α-chain CD25. These results indicate that negative regulating signals can modulate microdomains and suggest a general mechanism for inhibition of receptor signaling.

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“…As a positive control for immunoblotting, immunoprecipitation of IL-2R␣, IL-2R␤, and IL-2R␥ was performed as described previously. 18 Immunoprecipitates or 150 Lfractions from sucrose gradients were resolved by sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE). Western blot analysis was performed using polyclonal rabbit anti-IL-2R␣, IL-2R␤, and IL-2R␥ (Santa Cruz Biotechnology, Santa Cruz, CA) followed by Protein-A-HRP.…”

Section: Immunoprecipitations and Immunoblottingmentioning

confidence: 99%

“…18 In addition, IL-2-induced signaling was inhibited in these circumstances. These results were consistent with a signaling defect in the responsiveness of T cells to endogenously produced IL-2.…”

Section: Immobilized Mabs Specific For Gpi-ap Inhibit Il-2-induced Prmentioning

confidence: 99%

Role for lipid rafts in regulating interleukin-2 receptor signaling

Marmor

Julius

2001

Blood

Self Cite

114

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IntroductionLipid rafts are plasma membrane microdomains postulated to function in signaling and membrane trafficking. [1][2][3] Lipid rafts are enriched in gangliosides (glycosphingolipids) and cholesterol, which form liquid-ordered domains of decreased membrane fluidity. The long, saturated acyl chains of gangliosides impart a high degree of order further stabilized by intercalating cholesterol molecules, leading to the insolubility of lipid rafts in nonionic detergents. Lipid rafts can be isolated based on their detergent insolubility and low-buoyancy density using discontinuous sucrose gradient ultracentrifugation of nonionic detergent lysates. Lipid rafts are not artifacts of detergent extraction. They have been detected in living cells using chemical cross-linking and fluorescence resonance energy transfer. 4,5 The modification of proteins with saturated acyl groups can result in their localization within lipid rafts. Thus, these microdomains are enriched in glycosyl-phosphatidyl-inositol anchored proteins (GPI-AP) and in many signaling molecules such as Src family protein tyrosine kinases (PTKs), the adaptor protein LAT, heterotrimeric and small G-proteins, and phosphoinositides. 3 In addition, several transmembrane receptors are inducibly recruited to or stabilized within lipid rafts, including T-cell receptor (TCR), B-cell receptor (BCR), and Fc⑀RI. 2 Subsequent activation of signaling molecules in lipid rafts may facilitate signaling through these immunoreceptors. Lipid rafts may act to segregate molecules in the plasma membrane and to regulate signaling through the spatial coordination of intermolecular associations.Stimulation of T cells through TCR results in the activation of multiple signaling pathways, leading to interleukin-2 (IL-2) responsiveness and the secretion of IL-2 and resulting in autocrine cell growth. 6 The high-affinity receptor for IL-2 is composed of the IL-2R␣ chain, which functions solely in IL-2 binding, and IL-2R␤ and IL-2R␥ c , which contribute to IL-2 binding and mediate signal transduction. 7 IL-2-induced proliferation requires activation of the Janus family kinases JAK1 and JAK3, which are constitutively associated with IL-2R␤ and IL-2R␥, respectively. 8,9 Ligandinduced IL-2R aggregation leads to the juxtaposition of JAK1 and JAK3, resulting in their phosphorylation and activation. Subsequent phosphorylation of tyrosine residues in receptor chains leads to the SH2-domain-mediated recruitment of signal transducer and activator of transcription (STAT) proteins STAT5a and STAT5b. 7 JAK-mediated phosphorylation of STAT proteins leads to their dimerization by SH2 domain-phosphotyrosine interactions and their translocation to the nucleus, where STAT proteins regulate gene transcription. Signaling through the IL-2R also induces the recruitment and activation of phosphatidylinositol 3 kinase (PI3K), which is implicated in IL-2-mediated proliferation and survival through its downstream effector protein kinase B/Akt. 10,11 In addition, the tyrosine phosphorylation of IL-2R␤ results i...

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Immobilization of glycosylphosphatidylinositol-anchored proteins inhibits T cell growth but not function

Cited by 27 publications

References 58 publications

Functional Implication of Cellular Prion Protein in Antigen-Driven Interactions between T Cells and Dendritic Cells

Functional Implication of Cellular Prion Protein in Antigen-Driven Interactions between T Cells and Dendritic Cells

Selective Inhibition of T Cell Activation Via CD147 Through Novel Modulation of Lipid Rafts

Role for lipid rafts in regulating interleukin-2 receptor signaling

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