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

Tobias Longin Haas, Gudrun Strauss, Jonathan A. Lindquist, Nathalie Arhel, Edward Felder, Sabine Karl, Simone Fulda, Henning Walczak, Frank Kirchhoff, Klaus-Michael Debatin

Risultato della ricerca: Contributo in rivistaArticolo in rivista

28 Citazioni (Scopus)

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 originaleEnglish
pagine (da-a)1379-1393
Numero di pagine15
RivistaJOURNAL OF EXPERIMENTAL MEDICINE
Volume206
DOI
Stato di pubblicazionePubblicato - 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

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