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¹ University Children's Hospital Ulm, 89075 Ulm, Germany
² Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, 39120 Magdeburg, Germany
³ Institute of Virology and ⁴ Institute of General Physiology, University of Ulm, 89075 Ulm, Germany
⁵ Division of Apoptosis Regulation, German Cancer Research Center, 69120 Heidelberg, Germany
⁶ Department of Immunology, Division of Medicine, Imperial College London, London W12 ONN, UK

CORRESPONDENCE Gudrun Strauss: gudrun.strauss{at}uniklinik-ulm.de

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 -chain–associated protein of 70 kD, phospholipase-, and protein kinase C- into lipid rafts, thereby preventing their mutual tyrosine protein phosphorylation. Subsequently, Ca²⁺ mobilization and nuclear translocation of transcription factors NFAT, AP1, and NF-B 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.

Abbreviations used: AAD, amino-actinomycin-D; CD95L, CD95 ligand; DEVD, Asp-Glu-Val-Asp; EMSA, electrophoretic mobility shift assay; IETD, Ile-Glu-Thr-Asp; LAT, linker of activated T cells; m-CD95L, membrane-bound CD95L; MAPK, mitogen-activated protein kinase; PKC, protein kinase C; PLC, phospholipase C; SEE: staphylococcal enterotoxin E; Z-VAD.fmk, Z-Val-Ala-DL-Asp-fluoromethylketone; ZAP70, -chain–associated protein of 70 kD.

© 2009 Strauss et al.
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This article has been cited by other articles:

• Strauss, G., Lindquist, J. A., Arhel, N., Felder, E., Karl, S., Haas, T. L., Fulda, S., Walczak, H., Kirchhoff, F., Debatin, K.-M. (2009). CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling. JCB 185: i13-i13 [Full Text]  

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