Modulation of CD4+ T-cell activation by CD95 co-stimulation.
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.
Christian-Albrechts-University of Kiel, Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Strasse 3, Building 17, D-24105 Kiel, Germany.
M
M
Paulsen
S
S
Valentin
B
B
Mathew
S
S
Adam-Klages
U
U
Bertsch
I
I
Lavrik
P H
PH
Krammer
D
D
Kabelitz
O
O
Janssen
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D055767:Immobilized Proteins / Q000737:chemistry / Q000494:pharmacology; D008213:Lymphocyte Activation; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D019014:fas Receptor / Q000819:agonists / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D018797:Cell Cycle Proteins; D016207:Cytokines; D053222:Fas Ligand Protein; D020662:Guanine Nucleotide Exchange Factors; D055767:Immobilized Proteins; D009687:Nuclear Proteins; C062521:RCC1 protein, human; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases