CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling.
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 zeta-chain-associated protein of 70 kD, phospholipase-gamma, and protein kinase C- into lipid rafts, thereby preventing their mutual tyrosine protein phosphorylation. Subsequently, Ca(2+) mobilization and nuclear translocation of transcription factors NFAT, AP1, and NF-kappaB 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 antigen-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.
Strauss
Gudrun
G
University Children's Hospital Ulm, 89075 Ulm, Germany. gudrun.strauss@uniklinik-ulm.de
Lindquist
Jonathan A
JA
Arhel
Nathalie
N
Felder
Edward
E
Karl
Sabine
S
Haas
Tobias L
TL
Fulda
Simone
S
Walczak
Henning
H
Kirchhoff
Frank
F
Debatin
Klaus-Michael
KM
D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004789:Enzyme Activation; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D021962:Membrane Microdomains / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019014:fas Receptor / Q000235:genetics / Q000276:immunology*
D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D053222:Fas Ligand Protein; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases