Abstract
CD95 is a multifunctional receptor that induces cell death or proliferation depending on the signal, cell type, and cellular context. Here, we describe a thus far unknown function of CD95 as a silencer of T cell activation. Naive human T cells triggered by antigen-presenting cells expressing a membrane-bound form of CD95 ligand (CD95L) or stimulated by anti-CD3 and -CD28 antibodies in the presence of recombinant CD95L had reduced activation and proliferation, whereas preactivated, CD95-sensitive T cells underwent apoptosis. Triggering of CD95 during T cell priming interfered with proximal T cell receptor signaling by inhibiting the recruitment of ζ-chain-associated protein of 70 kD, phospholipase-γ, and protein kinase C-θ into lipid rafts, thereby preventing their mutual tyrosine protein phosphorylation. Subsequently, Ca 2+ mobilization and nuclear translocation of transcription factors NFAT, AP1, and NF-κB were strongly reduced, leading to impaired cytokine secretion. CD95-mediated inhibition of proliferation in naive T cells could not be reverted by the addition of exogenous interleukin-2 and T cells primed by CD95 co-stimulation remained partially unresponsive upon secondary T cell stimulation. HIV infection induced CD95L expression in primary human antigeen-presenting cells, and thereby suppressed T cell activation, suggesting that CD95/CD95L-mediated silencing of T cell activation represents a novel mechanism of immune evasion. © 2009 Strauss et al.
Lingua originale | Inglese |
---|---|
pagine (da-a) | 1379-1393 |
Numero di pagine | 15 |
Rivista | Journal of Experimental Medicine |
Volume | 206 |
DOI | |
Stato di pubblicazione | Pubblicato - 2009 |
Keywords
- Animals
- Antigen-Presenting Cells
- Antigens, CD28
- Antigens, CD3
- Antigens, CD95
- Caspases
- Cell Proliferation
- Cells, Cultured
- Cytokines
- Enzyme Activation
- Fas Ligand Protein
- HIV-1
- Humans
- Immunology
- Immunology and Allergy
- Lymphocyte Activation
- Membrane Microdomains
- Mitogen-Activated Protein Kinases
- Receptors, Antigen, T-Cell
- Signal Transduction
- T-Lymphocytes