Apoptosis in the immune system: 1. Fas-induced apoptosis in monocytes-derived human dendritic cells.
Dendritic cells (DC) are cells of the hematopoietic system specialized in capturing antigens and initiating T cell-mediated immune responses. We show here that human DC generated from adherent peripheral blood mononuclear cells (PBMC) after in vitro stimulation with granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) express Fas antigen (APO-1, CD95) and can undergo apoptosis upon triggering of Fas by monoclonal antibodies. Immature monocytes-derived dendritic cells (MDDC) upregulate CD86 and HLA-DR expression and develop dendrites and veiled processes. Flow cytometry analysis revealed CD95 expression in approx. 40% of these MDDC and incubation with anti-CD95 mAb (0.5 microg/ml) induced apoptosis when compared to untreated controls. The extent of apoptosis induced by the agonist anti-Fas antibody strongly related to the percentage of cells expressing CD 95. Upon tumor necrosis factor alpha (TNF-alpha) additional stimulation, MDDC assumed a characteristic mature dendritic cells morphology showing prolonged veils, CD83 expression, and high levels of HLA-DR. These cells have downregulated their Fas receptors (to approx. 20%) and undergo apoptosis to a lesser extent when treated with anti-CD 95, as demonstrated by the hardly noticeable effect of this antibody on the viability of cultured cells as compared to controls. Thus, upon TNF-alpha induced maturation, MDDC became resistant to Fas-induced apoptosis. The apoptotic episodes surrounding the earlier stage of DC differentiation appeared to be mediated by Fas. In contrast, a Fas independent pathway is probably responsible for the apoptotic events associated with terminally differentiated DC.
Nat
Roxana
R
Division of Cellular and Molecular Medicine, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania. rnat@univermed-cdgm.ro
Radu
E
E
Regalia
T
T
Popescu
L M
LM
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000954:Antigens, Surface / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D009000:Monocytes / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D019014:fas Receptor / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000954:Antigens, Surface; D006684:HLA-DR Antigens; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor