TRAIL (Apo2 ligand) and TWEAK (Apo3 ligand) mediate CD4(+) T cell killing of antigen-presenting macrophages

The human marrow produces similar to 10(10) monocytes daily, and this produ ction must be balanced by a similar rate of destruction. Monocytes/macropha ges can undergo apoptosis after activating CD4(+) T cells, suggesting one m echanism that may contribute to macrophage homeostasis. Previous reports in dicate that Fas-Fas ligand interactions are the principle molecules mediati ng this response. However, D10, an Ia(k)-resticted cloned Th2 line, will si milarly induce apoptosis in Ag-presenting macrophages, and D10 cells lack F as ligand, To confirm that D10 cells kill macrophages through Fas-independe nt pathways, D10 cells were shown to kill MRL lpr/lpr (Ia(k)) macrophages i n an Ag-dependent fashion, indicating additional mechanisms. Recent reports demonstrate that TNF-related apoptosis-inducing ligand (TRAIL), interactin g with Apo2, and TNF-like weak inducer of apoptosis (TWEAK), interacting wi th Apo3, will induce apoptosis in some cells. Using Abs to TRAIL and an Apo 3 IgG Fc fusion protein, we demonstrated that D10 cells express both TRAIL and TWEAK. The Apo3 fusion protein, but not human IgG, inhibited D10-induce d macrophage apoptosis, as did anti-TRAIL. Further studies demonstrated tha t AE7, a cloned Th1 line, and splenic T cells express TWEAK, TRAIL, and Fas ligand, and inhibiting these molecules also inhibited macrophage killing. These results indicate that D10 cells induce macrophage apoptosis through T RAIL- and TWEAK-dependent pathways. Because normal T cells also express the se molecules, these results support the concept that T cells have multiple pathways by which to induce macrophage apoptosis, These pathways may be imp ortant in immune processes such as macrophage homeostasis as well as in dow n-regulation of immune responses and elimination of macrophages infected wi th intracellular organisms.