Membrane-bound CD95 ligand expressed on human antigen-presenting cells prevents alloantigen-specific T cell response without impairment of viral and third-party T cell immunity

Strauß, Gudrun; Osen, Wolfram; Knape, Ingrid; Em, Jacobsen; Muller, Sylviane; Debatin, Klaus‐Michael

doi:10.1038/sj.cdd.4402019

Cited by 12 publications

(20 citation statements)

References 42 publications

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“…Although Ag-independent T cell proliferation induced by anti-CD3/28 activation was inhibited by TRAIL to nearly 100%, inhibition of alloantigen-specific proliferation ranged between 25% and 60%. This might be due to the fact that Ag and TRAIL were not expressed on the same APC, because we could show earlier in the CD95/CD95L system that development of alloantigenspecific CTLs is prevented only if APCs coexpressed the alloantigen together with the death ligand CD95L (40). In addition, costimulation of TRAIL-R in T cells derived from patients with OS prevented CD3/28-induced T cell activation, proliferation, and cytokine secretion, suggesting that also proliferation of autoreactive T cells can be prevented by simultaneous activation of TCR, CD28, and TRAIL-R.…”

Section: Discussionmentioning

confidence: 98%

TRAIL–Receptor Costimulation Inhibits Proximal TCR Signaling and Suppresses Human T Cell Activation and Proliferation

Lehnert¹,

Weiswange²,

Jeremias

et al. 2014

The Journal of Immunology

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The TRAIL–receptor/TRAIL system originally described to induce apoptosis preferentially in malignant cells is also known to be involved in T cell homeostasis and the response to viral infections and autoimmune diseases. Whereas the expression of TRAIL on activated NK and T cells increases their cytotoxicity, induction of TRAIL on APCs can turn them into apoptosis inducers but might also change their immunostimulatory capacity. Therefore, we analyzed how TRAIL–receptor (TRAIL–R) costimulation is modulating TCR-mediated activation of human T cells. T cells triggered by rTRAIL in combination with anti-CD3 and -CD28 Abs exhibited a strong decrease in the expression of activation markers and Th1 and Th2 cytokines compared with CD3/CD28-activated T cells. Most importantly, proliferation of TRAIL–R costimulated T cells was strongly impaired, but no apoptosis was induced. Addition of exogenous IL-2 could not rescue T cells silenced by TRAIL–R costimulation, and TRAIL-mediated inhibition of T cell proliferation only prevented TCR-triggered proliferation but was ineffective if T cells were activated downstream of the TCR. Inhibition of T cell proliferation was associated with abrogation of proximal TCR signaling by inhibiting recruitment of TCR-associated signaling molecules to lipid rafts, followed by abrogation of protein tyrosine phosphorylation of ZAP70, phospholipase C-γ1, and protein kinase C-θ, and impaired nuclear translocation of NFAT, AP-1, and NF-κB. Most importantly, TRAIL–R costimulation efficiently inhibited alloantigen-induced T cell proliferation and CD3/28-induced activation and proliferation of autoreactive T cells derived from patients with Omenn syndrome, indicating that coactivation of TRAIL–R and TCR represents a mechanism to downmodulate T cell immune responses.

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Section: Discussionmentioning

confidence: 98%

TRAIL–Receptor Costimulation Inhibits Proximal TCR Signaling and Suppresses Human T Cell Activation and Proliferation

Lehnert¹,

Weiswange²,

Jeremias

et al. 2014

The Journal of Immunology

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“…All cell lines were grown in complete RPMI 1640 medium (Invitrogen) supplemented with 10% FCS (Lonza), 2 mM l-glutamine, and 1 mM sodium pyruvate at 37°C in a humidified atmosphere containing 7.5% CO 2 . Establishment of C1R.A1.puro and C1R.A1.CD95L cells were described previously (25). T cells were cultured in complete RPMI 1640 medium supplemented with 2% FCS.…”

Section: Methodsmentioning

confidence: 99%

“…Although naive T cells are CD95 resistant, CD95 sensitivity develops 6-7 d after T cell activation (26). We have previously shown that expression of a noncleavable m-CD95L and HLA-A1 on APCs efficiently prevents development of HLA-A1-specific T cells in long-term T cell cultures in vitro (25). In this study, we analyze whether CD95L-expressing APCs in fact delete antigen-specific T cells or whether CD95 triggering instead prevents antigen-specific T cell priming in naive T cells.…”

mentioning

confidence: 99%

“…In this study, we analyze whether CD95L-expressing APCs in fact delete antigen-specific T cells or whether CD95 triggering instead prevents antigen-specific T cell priming in naive T cells. Therefore, we stimulated CFSE-labeled HLA-A1  T cells with the lymphoblastoid cell line C1R.A1.CD95L expressing the alloantigen HLA-A1 and m-CD95L (25). As controls, we used mock transfectant (C1R.A1.puro; HLA-A1 + and m-CD95L  ) or medium.…”

mentioning

confidence: 99%

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CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling

Strauß¹,

Lindquist²,

Arhel³

et al. 2009

J Cell Biol

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“…3,4 However, the molecular mechanisms of this co-stimulatory function have never been elucidated. Recently, Strauss et al 12,18 reported that CD95 co-stimulation blocks the activation of naïve T cells by inhibiting TCR signaling. This is in line with our observations using high concentrations of CD95 agonists, and thus reflects the inhibitory branch of CD95 signaling.…”

Section: Modulation Of Primary T-cell Activation By Cd95mentioning

confidence: 99%

Modulation of CD4+ T-cell activation by CD95 co-stimulation

et al. 2010

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CD95 is a dual-function receptor that exerts pro-or antiapoptotic effects depending on the cellular context, the state of activation, the signal threshold and the mode of ligation. In this study, we report that CD95 engagement modulates TCR/CD3-driven signaling pathways in resting T lymphocytes in a dose-dependent manner. While high doses of immobilized CD95 agonists silence T cells, lower concentrations augment activation and proliferation. We analyzed the co-stimulatory capacity of CD95 in detail in resting human CD4 þ T cells, and demonstrate that low-dose ligand-induced co-internalization of CD95 and TCR/CD3 complexes enables non-apoptotic caspase activation, the prolonged activation of MAP kinases, the upregulation of antiapoptotic proteins associated with apoptosis resistance, and the activation of transcription factors and cell-cycle regulators for the induction of proliferation and cytokine production. We propose that the levels of CD95L on antigen-presenting cells (APCs), neighboring T cells or epithelial cells regulate inhibitory or co-stimulatory CD95 signaling, which in turn is crucial for fine-tuning of primary T-cell activation. Cell Death and Differentiation (2011) 18, 619-631; doi:10.1038/cdd.2010.134; published online 5 November 2010For activation of resting T cells, two signals are required. The first signal emerges from an engagement of the T cell receptor (TCR)/CD3 complex, whereas the second signal is generated through the ligation of co-stimulatory receptors (i.e. CD28). Recently, 'tumor necrosis factor (TNF) receptor-associated factor' (TRAF) binding receptors were identified as a second class of co-stimulatory receptors. 1 As an example, Alderson et al. 2,3 provided first evidence for the role of CD95 (Fas, APO-1), the prototypic death receptor of the immune system, in the activation of human T cells. It was subsequently reported that CD3-crosslinking alone or CD3/CD95 costimulation induces the processing of caspase-8 and/or caspase-3 as a prerequisite for full T-cell proliferation. [4][5][6] CD95 co-ligation also influences several other routes of intracellular signal transduction. Kataoka et al. 7 reported the activation of NF-kB-and mitogen-activated protein kinase (MAPK)-related pathways following an interaction of CD95-recruited 'cellular FLICE-inhibitory protein' (cFLIP) with downstream signaling molecules. Apparently, this process required the cleavage of cFLIP into a p43 fragment. More recently, however, it was argued that p22-FLIP (but not p43) can activate NF-kB by directly interacting with the IKK complex. 8 So far, three cFLIP isoforms (cFLIP L , cFLIP S and cFLIP R ) were identified, with cFLIP S/R mediating a block in apoptosis by inhibiting procaspase-8 at the death-inducing signaling complex (DISC). The role of cFLIP L regarding an inhibition at the DISC is still a matter of debate. 8,9 Further downstream, antiapoptotic proteins including Bcl-2/Bcl-X L and 'X-linked inhibitor-of-apoptosis protein' (XIAP) may prevent apoptosis. 9,10 A decreased expression of antiapoptotic c...

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Membrane-bound CD95 ligand expressed on human antigen-presenting cells prevents alloantigen-specific T cell response without impairment of viral and third-party T cell immunity

Cited by 12 publications

References 42 publications

TRAIL–Receptor Costimulation Inhibits Proximal TCR Signaling and Suppresses Human T Cell Activation and Proliferation

TRAIL–Receptor Costimulation Inhibits Proximal TCR Signaling and Suppresses Human T Cell Activation and Proliferation

CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling

Modulation of CD4+ T-cell activation by CD95 co-stimulation

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