Sensitizing antigen-specific CD8+ T cells for accelerated suicide causes immune incompetence

Wasem, Christoph; Arnold, Diana; Saurer, Leslie; Corazza, Nadia; Jakob, Sabine; Herren, Simon; Vallan, Claudio; Mueller, Christoph; Brunner, Thomas

doi:10.1172/jci200316344

Cited by 6 publications

(5 citation statements)

References 45 publications

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“…Therefore, PKC inhibitors increased the sensitivity of Jurkat cells to Fasmediated apoptosis either without FasL exposure (induced by endogen FasL expressed on Jurkat cell membranes) or in presence of soluble FasL added to culture medium. However, as bisindolylmaleimide VIII is a selective PKC inhibitor that could also act on other intracellular pathway [31,59], we verified that 116 kDa Fas aggregate phosphorylation was selectively inhibited by the specific PKC pseudosubstrate 19-36 which cannot penetrate through the plasma membrane [32]. These data show that ecto-PKC regulated the spontaneous oligomerization of Fas receptors in the absence of FasL to form pre-associated Fas complexes.…”

Section: Discussionsupporting

confidence: 52%

Increase of Fas-induced apoptosis by inhibition of extracellular phosphorylation of Fas receptor in Jurkat cell line

Lautrette¹,

Loum-Ribot²,

Petit³

et al. 2006

Apoptosis

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Apoptosis signalling through the Fas pathway requires several steps of aggregation of the Fas receptor in the membrane, including aggregation that may occur in the absence of Fas ligand. Association of Fas domains is determinant to signal transmission following Fas ligand binding to a specific domain. The domains involved in Fas aggregation are located in its extracellular region and contain three potential protein kinase C-binding motifs. We therefore studied the possibility that phosphorylation of the extracellular region of Fas might be implicated in the regulation of Fas-mediated apoptosis. Inhibition experiments of extracellular phosphorylation were performed in human Jurkat T leukemia cells with K252b, an impermeant protein-kinase inhibitor. Extracellular phosphorylation of Fas receptor was related to ecto-kinase, as assessed by the [gamma-(32)P] ATP labelling of Fas-116 kDa aggregates, suppressed by K252b inhibitor which significantly increased the sensitivity to Fas-mediated apoptosis. Ecto-PKC involvement was demonstrated by bisindolylmaleimide VIII, a selective inhibitor of protein kinase C which significantly increased both Fas aggregation in the membrane and Fas-mediated apoptosis and by the addition of the PKC pseudo-substrate 19-36 which inhibited the phosphorylation of 116 kDa Fas aggregates. These data support a role for Fas phosphorylation in the decreased sensitivity to apoptosis in the Jurkat T leukemia cell line.

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Section: Discussionsupporting

confidence: 52%

Increase of Fas-induced apoptosis by inhibition of extracellular phosphorylation of Fas receptor in Jurkat cell line

Lautrette¹,

Loum-Ribot²,

Petit³

et al. 2006

Apoptosis

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“…For characterization and intracellular staining, T cells were isolated from spleen and mesenteric lymph node and stained as described above. Virus titers were analyzed in different organs using plaque assay, as described previously (41). For the detection of virus-specific cytotoxic T cells, EL4 thymoma cells were labeled with 3 H-thymidine (10 Ci/ml) overnight and pretreated with gp33 or adn5 peptide.…”

Section: Lcmv Infection and Virus-specific T Cell Cytotoxicitymentioning

confidence: 99%

The orphan nuclear receptor LRH-1/NR5a2 critically regulates T cell functions

et al. 2019

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LRH-1 (liver receptor homolog-1/NR5a2) is an orphan nuclear receptor, which regulates glucose and lipid metabolism, as well as intestinal inflammation via the transcriptional control of intestinal glucocorticoid synthesis. Predominantly expressed in epithelial cells, its expression and role in immune cells are presently enigmatic. LRH-1 was found to be induced in immature and mature T lymphocytes upon stimulation. T cell–specific deletion of LRH-1 causes a drastic loss of mature peripheral T cells. LRH-1–depleted CD4+ T cells exert strongly reduced activation-induced proliferation in vitro and in vivo and fail to mount immune responses against model antigens and to induce experimental intestinal inflammation. Similarly, LRH-1–deficient cytotoxic CD8+ T cells fail to control viral infections. This study describes a novel and critical role of LRH-1 in T cell maturation, functions, and immopathologies and proposes LRH-1 as an emerging pharmacological target in the treatment of T cell–mediated inflammatory diseases.

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“…It has been reported that Bcl‐2 protein is up‐regulated in MG thymuses and it has been indicated to suppress thymocytic apoptosis, allowing MG autoreactive T cells to escape elimination 21,22 . cFLIP appears to prevent early death receptor‐mediated T cell apoptosis and over‐expression of cFLIP also supports the accumulation of autoreactive lymphocytes 39 . In addition, high levels of cFLIP expression may shift death receptor signalling from apoptosis induction towards cell‐activating signals and enhanced proliferation through activation of nuclear factor kappa‐b (NF‐κB) 39,40 .…”

Section: Discussionmentioning

confidence: 99%

“…21,22 cFLIP appears to prevent early death receptor-mediated T cell apoptosis and over-expression of cFLIP also supports the accumulation of autoreactive lymphocytes. 39 In addition, high levels of cFLIP expression may shift death receptor signalling from apoptosis induction towards cell-activating signals and enhanced proliferation through activation of nuclear factor kappa-b (NF-jB). 39,40 Thus, in addition to enhancing death receptor-mediated apoptosis, downregulation of cFLIP by dual APL treatment in T cells may also limit the proinflammatory activating effect of deathreceptor signalling.…”

Section: Discussionmentioning

confidence: 99%

“…39 In addition, high levels of cFLIP expression may shift death receptor signalling from apoptosis induction towards cell-activating signals and enhanced proliferation through activation of nuclear factor kappa-b (NF-jB). 39,40 Thus, in addition to enhancing death receptor-mediated apoptosis, downregulation of cFLIP by dual APL treatment in T cells may also limit the proinflammatory activating effect of deathreceptor signalling. Further, the absence of autocrine IL-2 production in the CD4 + CD25 + T regulatory cells is known to favour the expression of anti-apoptotic proteins and apoptosis inhibitors, while autocrine IL-2 production in CD4 + CD25 -T cells may up-regulate the expression of pro-apoptotic proteins and suppress inhibitor expression.…”

Section: Discussionmentioning

confidence: 99%

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A dual altered peptide ligand down‐regulates myasthenogenic T cell responses and reverses experimental autoimmune myasthenia gravis via up‐regulation of Fas–FasL‐mediated apoptosis

et al. 2006

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SummaryMyasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T cell-dependent, antibody-mediated autoimmune diseases. A dual altered peptide ligand (APL) that is composed of the tandemly arranged two single amino acid analogues of two myasthenogenic peptides, p195-212 and p259-271, was demonstrated to down-regulate in vitro and in vivo MG-associated autoreactive responses. The aims of this study were to investigate the possible role of Fas-FasL-mediated apoptosis in the downregulatory mechanism of the dual APL. We demonstrate here the effect of the dual APL on expression of key molecules involved in the Fas-FasL pathway, in a p195-212-specific T cell line, in mice immunized with Torpedo acetylcholine receptor and in mice afflicted with EAMG (induced with the latter). In vitro and in vivo results show that the dual APL up-regulated expression of Fas and FasL on the CD4 cells. Expression of the pro-apoptotic molecules, caspase 8 and caspase 3, was significantly up-regulated, while anti-apoptotic cFLIP and Bcl-2 were down-regulated upon treatment with the dual APL. The dual APL also increased phosphorylation of the mitogen-activated protein kinases, c-Jun-NH2-terminal kinase and p-38, known to play a role in the regulation of FasL expression. Further, in the T cell line incubated with the dual APL as well as in mice of the SJL inbred strain immunized with the myasthenogenic peptide and treated concomitantly with the dual APL, the percentage of apoptotic cells increased. Results strongly indicate that up-regulation of apoptosis via the Fas-FasL pathway is one of the mechanisms by which the dual APL reverses EAMG manifestations in C57BL/6 mice.

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Sensitizing antigen-specific CD8+ T cells for accelerated suicide causes immune incompetence

Cited by 6 publications

References 45 publications

Increase of Fas-induced apoptosis by inhibition of extracellular phosphorylation of Fas receptor in Jurkat cell line

Increase of Fas-induced apoptosis by inhibition of extracellular phosphorylation of Fas receptor in Jurkat cell line

The orphan nuclear receptor LRH-1/NR5a2 critically regulates T cell functions

A dual altered peptide ligand down‐regulates myasthenogenic T cell responses and reverses experimental autoimmune myasthenia gravis via up‐regulation of Fas–FasL‐mediated apoptosis

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