Dendritic cells are resistant to apoptosis through the Fas (CD95/APO-1) pathway

D Ashany, A Savir, N Bhardwaj… - The Journal of …, 1999 - journals.aai.org
D Ashany, A Savir, N Bhardwaj, KB Elkon
The Journal of Immunology, 1999journals.aai.org
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 …
Abstract
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-γ and/or TNF-α 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.
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