CD28 signals through acidic sphingomyelinase.

Boucher, Louis-Martin; Wiegmann, Katja; Fütterer, Agnes; Pfeffer, Klaus; Machleidt, Thomas; Schütze, Stefan; Mak, Tak W.; Krönke, Martin

doi:10.1084/jem.181.6.2059

Cited by 180 publications

(102 citation statements)

References 53 publications

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“…This was particularly evident after ligation of CD28 (Fig. 9B), which promotes ASM activation and ceramide release in the outer leaflet of the plasma membrane (27). Supporting the hypothesis that the N 3 -C 6 -cer codistributed with endogenous ceramides released upon receptor ligation, pre-exposure of T cells to the ASM inhibitor amitriptyline largely prevented its redistribution into activation clusters after CD28 ligation (Fig.…”

Section: Incorporated N 3 -C 6 -Cer Does Not Affect T Cell Activationsupporting

confidence: 48%

“…Similarly, physiological acid SMase (ASM) activation after death receptor ligation followed by ceramide release interferes with relay of TCR signaling by abrogating store-operated Ca 2+ entry, NF-AT activation, and IL-2 synthesis (25,26). However, in other situations, activation of SMases appears to modulate T cell activation (27)(28)(29), indicating that both the amount and/or compartmentalization of ceramides at stimulatory interfaces needs to be tightly controlled. In support of this hypothesis, Ab-based detection studies have revealed that ceramides are largely excluded from the center of an established immune synapse (IS) in favor of the lamellum (29).…”

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confidence: 99%

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A Functionalized Sphingolipid Analogue for Studying Redistribution during Activation in Living T Cells

Collenburg

Walter

Burgert

et al. 2016

The Journal of Immunology

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Sphingolipids are major components of the plasma membrane. In particular, ceramide serves as an essential building hub for complex sphingolipids, but also as an organizer of membrane domains segregating receptors and signalosomes. Sphingomyelin breakdown as a result of sphingomyelinase activation after ligation of a variety of receptors is the predominant source of ceramides released at the plasma membrane. This especially applies to T lymphocytes where formation of ceramide-enriched membrane microdomains modulates TCR signaling. Because ceramide release and redistribution occur very rapidly in response to receptor ligation, novel tools to further study these processes in living T cells are urgently needed. To meet this demand, we synthesized nontoxic, azido-functionalized ceramides allowing for bio-orthogonal click-reactions to fluorescently label incorporated ceramides, and thus investigate formation of ceramide-enriched domains. Azido-functionalized C6-ceramides were incorporated into and localized within plasma membrane microdomains and proximal vesicles in T cells. They segregated into clusters after TCR, and especially CD28 ligation, indicating efficient sorting into plasma membrane domains associated with T cell activation; this was abolished upon sphingomyelinase inhibition. Importantly, T cell activation was not abrogated upon incorporation of the compound, which was efficiently excluded from the immune synapse center as has previously been seen in Ab-based studies using fixed cells. Therefore, the functionalized ceramides are novel, highly potent tools to study the subcellular redistribution of ceramides in the course of T cell activation. Moreover, they will certainly also be generally applicable to studies addressing rapid stimulation-mediated ceramide release in living cells.

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Section: Incorporated N 3 -C 6 -Cer Does Not Affect T Cell Activationsupporting

confidence: 48%

mentioning

confidence: 99%

A Functionalized Sphingolipid Analogue for Studying Redistribution during Activation in Living T Cells

Collenburg

Walter

Burgert

et al. 2016

The Journal of Immunology

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“…Three forms of SMases are candidates for SM hydrolysis. Acid SMase (pH optimum 4.5 ± 5.0) has been associated in apoptosis signaling triggered by TNFa (Wiegmann et al, 1994), antiFas (Cifone et al, 1994), and anti-CD28 (Boucher et al, 1995); activation of a membrane bound neutral SMase (pH optimum 7.4) has also been described with TNFa (Wiegmann et al, 1994), anti-Fas antibody (Tepper et al, 1995), IL-1b (Mathias et al, 1993) and daunorubicin ; finally, a cytosolic neutral SMase has been implicated in vitamin D3 induced differentiation (Okazaki et al, 1994). A recent study by Kolesnick's group clearly demonstrated that acid SMase-deficient human lymphoblasts as well as lung endothelium, thymus and spleen of acid SMase knockout mice are defective in IRinduced apoptosis (Santana et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Lack of ceramide generation in TF-1 human myeloid leukemic cells resistant to ionizing radiation

et al. 1998

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The mechanism(s) by which ionizing radiation (IR) induces cell death is of fundamental importance in understanding cell sensitivity and resistance. Here we evaluated the response to IR of two subclones of the autonomous human erythromyeloblastic cell line TF-1: TF-1-34 (which expresses CD34) and TF-1-33 (which lacks CD34). In clonogenic assays, TF-1-34 cells were found to be relatively less sensitive to IR compared to TF-1-33 cells based on the D 0 determination (3.01 vs 1.56 Gy). Furthermore, after IR at 12 Gy, TF-1-33 cell viability decreased by *50% within 24 h, whereas TF-1-34 cell growth was unaffected during this time. Gradual loss of TF-1-34 cell viability was observed only after 48 h. Morphological and molecular analysis revealed that TF-1-33 cells died of apoptosis, and TF-1-34 cells of delayed reproductive cell death. While IR produced comparable amounts of DNA double strand breaks (DSB) in both cell lines, TF-1-34 retained DSB much longer than TF-1-33 suggesting that radioresistance and the defective apoptotic response of TF-1-34 cells was not related to a higher DNA repair capacity. However, the lack of an apoptotic response in TF-1-34 was correlated to the absence of a sphingomyelin (SM)-ceramide (CER) signaling pathway. Indeed, IR triggered in TF-1-33 cells but not in TF-1-34, SM hydrolysis (25% at 12 Gy) and CER generation (450%) through the activation of neutral but not acid sphingomyelinase. Synthetic cell permeate CER induced apoptosis in both TF-1-33 and TF-1-34 cells. This study indicates that alterations of the SM-CER signaling pathway can significantly influence the cell death process as well as the survival of acute myeloid leukemia cells after IR exposure.

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“…indeed several mediators known to increase the intracellular levels of ceramide are involved in the early immune response, i.e., TCR triggering, IL-1␤, TNF-␣, IFN-␥, and CD28 ligation (10,(12)(13)(14)(15)(32)(33)(34). When the T cell forms Ag-specific conjugates with APC, a supramolecular activation cluster is observed at the T-APC contact zone.…”

Section: Discussionmentioning

confidence: 99%

“…Several pathways with the potential to increase PP2A activity exist in T cells during their encounter with APC. For instance, triggering of the TCR (10), CD5 (11), CD28 (12), and cytokine receptors for IL-1␤ (13) and TNF-␣ (14, 15) activates sphingomyelinase. Sphingomyelinase in turn hydrolyzes sphingomyelin to generate the lipid second messenger ceramide that is a potent activator of ceramide-activated protein phosphatase belonging to the PP2A family (16 -18).…”

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confidence: 99%

Ceramide-Induced TCR Up-Regulation

Menné

Lauritsen

Dietrich

et al. 2000

The Journal of Immunology

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The TCR is a constitutively recycling receptor meaning that a constant fraction of TCR from the plasma membrane is transported inside the cell at the same time as a constant fraction of TCR from the intracellular pool is transported to the plasma membrane. TCR recycling is affected by protein kinase C activity. Thus, an increase in protein kinase C activity affects TCR recycling kinetics leading to a new TCR equilibrium with a reduced level of TCR expressed at the T cell surface. Down-regulation of TCR expression compromises T cell activation. Conversely, TCR up-regulation is expected to increase T cell responsiveness. The purpose of this study was to identify and characterize potential pathways for TCR up-regulation. We found that ceramide affected TCR recycling dynamics and induced TCR up-regulation in a concentration- and time-dependent manner. Experiments applying phosphatase inhibitors indicated that ceramide-induced TCR up-regulation was most probably mediated by serine/threonine protein phosphatase 2A. Analyses of T cell variants demonstrated that TCR up-regulation was dependent on the presence of an intact CD3γ L-based motif and thus acted on TCR engaged in the recycling pathway. Finally, we showed that TCR up-regulation probably plays a physiological role by increasing T cell responsiveness. Thus, by affecting the TCR recycling kinetics, T cells have the potential both to up- and down-regulate TCR expression and thereby adjust T cell responsiveness.

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CD28 signals through acidic sphingomyelinase.

Cited by 180 publications

References 53 publications

A Functionalized Sphingolipid Analogue for Studying Redistribution during Activation in Living T Cells

A Functionalized Sphingolipid Analogue for Studying Redistribution during Activation in Living T Cells

Lack of ceramide generation in TF-1 human myeloid leukemic cells resistant to ionizing radiation

Ceramide-Induced TCR Up-Regulation

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