Dendritic cells are resistant to apoptosis through the Fas (CD95/APO-1) pathway.
Immunoregulation of lymphocytes and macrophages in the peripheral immune system is achieved in part by activation-induced cell death. Members of the TNF receptor family including Fas (CD95) are involved in the regulation of activation-induced cell death. To determine whether activation-induced cell death plays a role in regulation of dendritic cells (DCs), we examined interactions between Ag-presenting murine DCs and Ag-specific Th1 CD4+ T cells. Whereas mature bone marrow- or spleen-derived DCs expressed high levels of Fas, these DCs were relatively insensitive to Fas-mediated killing by the agonist mAb, Jo-2, as well as authentic Fas ligand expressed on the CD4+ T cell line, A.E7. The insensitivity to Fas-mediated apoptosis was not affected by priming with IFN-gamma and/or TNF-alpha or by blocking the DC survival signals TNF-related activation-induced cytokine and CD40L. However, apoptosis could be induced with C2-ceramide, suggesting that signals proximal to the generation of ceramide might mediate resistance to Fas. Analysis of protein expression of several anti-apoptotic mediators revealed that expression of the intracellular inhibitor of apoptosis Fas-associated death domain-like IL-1-converting enzyme-inhibitory protein was significantly higher in Fas-resistant DCs than in Fas-sensitive macrophages, suggesting a possible role for Fas-associated death domain-like IL-1-converting enzyme-inhibitory protein in DC resistance to Fas-mediated apoptosis. Our results demonstrate that murine DCs differ significantly from other APC populations in susceptibility to Fas-mediated apoptosis during cognate presentation of Ag. Because DCs are most notable for initiation of an immune response, resistance to apoptosis may contribute to this function.
Ashany
D
D
Hospital for Special Surgery, Cornell University Medical Center, New York 10021, USA. ashanyd@hss.edu
Savir
A
A
Bhardwaj
N
N
Elkon
K B
KB
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand; D002352:Carrier Proteins / Q000502:physiology; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D053222:Fas Ligand Protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D007113:Immunity, Innate; D008024:Ligands; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008817:Mice, Mutant Strains; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D019014:fas Receptor / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*
D019013:CD40 Antigens; D002352:Carrier Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D019014:fas Receptor; D023201:CD40 Ligand; D016178:Granulocyte-Macrophage Colony-Stimulating Factor