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.

Strauss, G., Lindquist, J. A., Arhel, N., Felder, E., Karl, S., Haas, T. L., Fulda, S., Walczak, H., Kirchhoff, F., Debatin, K., CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling, <<JOURNAL OF EXPERIMENTAL MEDICINE>>, 2009; 206 (6): 1379-1393. [doi:10.1084/jem.20082363] [http://hdl.handle.net/10807/114377]

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

Haas, Tobias L.;
2009

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.
Inglese
Strauss, G., Lindquist, J. A., Arhel, N., Felder, E., Karl, S., Haas, T. L., Fulda, S., Walczak, H., Kirchhoff, F., Debatin, K., CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling, <<JOURNAL OF EXPERIMENTAL MEDICINE>>, 2009; 206 (6): 1379-1393. [doi:10.1084/jem.20082363] [http://hdl.handle.net/10807/114377]
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