Abstract
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+ 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.
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Abbreviations
- abs:
-
absorbance
- AMC:
-
7-amino-4-methylcoumarin
- APC:
-
antigen-presenting cell
- Bcl-XL:
-
B-cell lymphoma-extra large
- BrdU:
-
bromodeoxyuridine
- CD95L:
-
CD95 ligand
- CDK:
-
cyclin-dependent kinase
- cFLIP:
-
cellular FLICE-inhibitory protein
- cFLIPS/R:
-
cFLIPshort/Raji
- cFLIPL:
-
cFLIPlong
- CFSE:
-
carboxy-fluorescein diacetate succinimidyl ester
- CTLA-4:
-
cytotoxic T-lymphocyte antigen-4
- CytD:
-
cytochalasin D
- DC:
-
dendritic cell
- DISC:
-
death-inducing signaling complex
- ERK:
-
extracellular signal-regulated protein kinase
- IFNγ:
-
interferon γ
- IκB:
-
inhibitor of NF-κB
- IL-2Rα/β:
-
interleukin-2 receptor α/β chain
- LatA:
-
latrunculin A
- LZ-CD95L:
-
leucin zipper CD95L
- mAb:
-
monoclonal antibody
- MAPK:
-
mitogen-activated protein kinase
- MFI:
-
mean fluorescence intensity
- NF-κB:
-
nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells
- PARP:
-
poly (ADP-ribose) polymerase
- PBMCs:
-
peripheral blood mononuclear cells
- PCNA:
-
proliferating cell nuclear antigen
- PD:
-
ERK1/2 inhibitor PD 98059
- PHA:
-
phytohemagglutinin
- PI:
-
propidium iodide
- PLCγ:
-
phospholipase Cγ
- PMA:
-
phorbol myristate acetate
- Rb:
-
retinoblastoma
- rIL-2:
-
recombinant IL-2
- TC:
-
tissue culture
- TCR:
-
T cell receptor
- TdR:
-
thymidine
- Th1:
-
T helper 1
- TNF:
-
tumor necrosis factor
- TNFR:
-
TNF receptor
- TRAF:
-
TNF receptor-associated factor
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Acknowledgements
This work forms part of the PhD thesis of M Paulsen. The project was sponsored by grants from the German Research Council (SFB 415, SFB 877) and the Medical Faculty of the Christian-Albrechts-University of Kiel.
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Paulsen, M., Valentin, S., Mathew, B. et al. Modulation of CD4+ T-cell activation by CD95 co-stimulation. Cell Death Differ 18, 619–631 (2011). https://doi.org/10.1038/cdd.2010.134
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DOI: https://doi.org/10.1038/cdd.2010.134
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