CD40 ligation counteracts Fas-induced apoptosis of human dendritic cells.
Dendritic cells (DC) are cells of the hematopoletic system specialized in capturing antigens and initiating T cell-mediated immune responses. We show here that human DC generated in vitro by culturing CD34+ cord blood progenitor cells in granulocyte macrophage colony stimulating factor plus tumor necrosis factor-alpha express the Fas antigen (APO-1, CD95) and undergo apoptosis upon triggering of Fas by mAb. However, only a proportion of the cells die in response to Fas ligation, an observation that may be related to the virtual absence of the bcl-2 protein in about half of the cells. Ligation of DC CD40 by culture on CD40L-transfected fibroblastic cells up-regulates the expression of bcl-2 and, concomitantly, renders DC virtually resistant to Fas-induced apoptosis. Parallel experiments with mature, interdigitating dendritic cells (IDC) isolated from tonsils revealed that IDC express Fas but do not enter into apoptosis following Fas ligation, a finding that may be explained by their high levels of bcl-2. Thus, upon encountering antigen-specific T cells, DC become resistant to Fas-induced apoptosis, as a consequence of CD40 ligation and possibly by mechanisms associated to the up-regulation of bcl-2 protein expression.
Björck
P
P
Schering-Plough Laboratory for Immunological Research, Dardilly, France.
Banchereau
J
J
Flores-Romo
L
L
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D019013:CD40 Antigens / Q000187:drug effects* / Q000502:physiology; D023201:CD40 Ligand; D002454:Cell Differentiation / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D018920:Coculture Techniques; D053938:DNA Fragmentation; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D005347:Fibroblasts; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000494:pharmacology*; D014066:Palatine Tonsil / Q000166:cytology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000276:immunology*
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D023201:CD40 Ligand; D016178:Granulocyte-Macrophage Colony-Stimulating Factor