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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 (0.5μg/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 α (TNF‐α) 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‐α 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.