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

Strauß, Gudrun; Lindquist, Jonathan A.; Arhel, Nathalie J.; Felder, Edward; Karl, Sabine; Haas, Tobias; Fulda, Simone; Walczak, Henning; Kirchhoff, Frank; Debatin, Klaus‐Michael

doi:10.1083/jcb1856oia13

Cited by 10 publications

(22 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…28,29 More recent data, however, provide evidence for alternate activities of APC-associated CD95L on naïve T cells, including the complete block of T-cell activation in the absence of apoptosis and proliferation. 12,28 This is in line with an earlier report by Chen et al, 30 who observed an inhibition of T-cell proliferation by 'CD95L-painted' K562/B7-1 cells that was only partially caused by apoptosis induction. However, in this study, a positive co-stimulatory effect of CD95L had not been noted.…”

Section: Modulation Of Primary T-cell Activation By Cd95supporting

confidence: 81%

“…32 It was suggested that macrophages upregulate CD95L during HIV infection 33 and thereby contribute to the apoptotic depletion of uninfected CD4 þ T cells. According to the report by Strauss et al, 12 another mechanism of reducing T-cell numbers might be the proliferation block of resting cells. Apparently, the outcome of CD95 ligation very much depends on the state of activation of the respective T-cell population.…”

Section: Modulation Of Primary T-cell Activation By Cd95mentioning

confidence: 99%

“…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%

“…24 Notably, TCR silencing in the presence of high amounts of CD95L is associated with a complete inhibition of CD3/CD28-mediated ERK activation. 12 Circumventing TCR ligation with phorbolester and calcium ionophore indicates that CD95 ligation affects TCR signaling upstream or independent of calcium mobilization and PKC activation.…”

Section: Modulation Of Primary T-cell Activation By Cd95mentioning

confidence: 99%

“…As this differential signaling capacity was seen for different ligands, it points to a novel mechanism to regulate T-cell activation in a contextspecific manner. In addition to the inhibitory effect (recently described by Strauss et al 12 ) we provide a detailed analysis of signaling events associated with the positive co-stimulatory function of CD95. We demonstrate that CD95 ligation with low doses of agonists promotes TCR-triggered MAPK phosphorylation, non-apoptotic caspase activation, and the upregulation of activation markers and antiapoptotic checkpoint proteins.…”

mentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2010

View full text Add to dashboard Cite

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...

show abstract

Section: Modulation Of Primary T-cell Activation By Cd95supporting

confidence: 81%

Section: Modulation Of Primary T-cell Activation By Cd95mentioning

confidence: 99%

Section: Modulation Of Primary T-cell Activation By Cd95mentioning

confidence: 99%

Section: Modulation Of Primary T-cell Activation By Cd95mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2010

View full text Add to dashboard Cite

show abstract

CD95-mediated cell signaling in cancer: mutations and post-translational modulations

Tauzin

Debure

Moreau

et al. 2011

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Apoptosis has emerged as a fundamental process important in tissue homeostasis, immune response, and during development. CD95 (also known as Fas), a member of the tumor necrosis factor receptor (TNF-R) superfamily, has been initially cloned as a death receptor. Its cognate ligand, CD95L, is mainly found at the plasma membrane of activated T-lymphocytes and natural killer cells where it contributes to the elimination of transformed and infected cells. According to its implication in the immune homeostasis and immune surveillance, and since several malignant cells of various histological origins exhibit loss-of-function mutations, which cause resistance towards the CD95-mediated apoptotic signal, CD95 has been classified as a tumor suppressor gene. Nevertheless, this assumption has been recently challenged, as in certain pathophysiological contexts, CD95 engagement transmits non-apoptotic signals that promote inflammation, carcinogenesis or liver/peripheral nerve regeneration. The focus of this review is to discuss these apparent contradictions of the known function(s) of CD95.

show abstract

In vitro-established alloantigen-specific CD8+ CTLs mediate graft-versus-tumor activity in the absence of graft-versus-host disease

et al. 2011

View full text Add to dashboard Cite

Mature donor-derived T cells in allogeneic bone marrow (BM) transplants mediate the graft-versus-tumor (GVT) effect by recognizing alloantigens on leukemic cells. However, alloantigen reactivity towards non-malignant tissues also induces graft-versus-host disease (GVHD). Defining T-cell subpopulations that mediate the GVT effect in the absence of GVHD induction remains a major challenge in allogeneic BM transplantation. In this study, we show that in vitro-generated alloantigen-specific CD8 þ cytotoxic T cells (CTLs) established by weekly stimulation with alloantigen-expressing antigenpresenting cells did not induce GVHD in two major histocompatibility complex-mismatched BM transplantation models, where induction of lethal GVHD is dependent on the presence of either CD4 þ or CD8 þ T cells. Despite their strong alloantigen specificity, transplantation of CTLs did not induce the expression of GVHD-associated cytokines IFN-c and TNF-a or clinical or histological signs of GVHD, and lead to a survival rate of above 90%. However, transplantation of unstimulated CD8 þ T cells, which were not primed by the alloantigen in vitro, induced GVHD in both the transplantation models. Although CTLs were impaired in GVHD induction, they efficiently eradicated Bcr-Abl-transformed B-cell leukemias or mastocytomas. Thus, in vitro-derived CTLs might be useful for optimizing anti-tumor therapy in the absence of GVHD induction.

show abstract

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

Cited by 10 publications

References 44 publications

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

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

CD95-mediated cell signaling in cancer: mutations and post-translational modulations

In vitro-established alloantigen-specific CD8+ CTLs mediate graft-versus-tumor activity in the absence of graft-versus-host disease

Contact Info

Product

Resources

About