Kaplan M J, Ray D, Mo R R, Yung R L, Richardson B C
Department of Medicine, University of Michigan, and Veterans Affairs Medical Center, Ann Arbor MI 48109, USA.
J Immunol. 2000 Mar 15;164(6):2897-904. doi: 10.4049/jimmunol.164.6.2897.
The human marrow produces approximately 1010 monocytes daily, and this production must be balanced by a similar rate of destruction. Monocytes/macrophages can undergo apoptosis after activating CD4+ T cells, suggesting one mechanism that may contribute to macrophage homeostasis. Previous reports indicate that Fas-Fas ligand interactions are the principle molecules mediating this response. However, D10, an Iak-restricted cloned Th2 line, will similarly induce apoptosis in Ag-presenting macrophages, and D10 cells lack Fas ligand. To confirm that D10 cells kill macrophages through Fas-independent pathways, D10 cells were shown to kill MRL lpr/lpr (Iak) macrophages in an Ag-dependent fashion, indicating additional mechanisms. Recent reports demonstrate that TNF-related apoptosis-inducing ligand (TRAIL), interacting with Apo2, and TNF-like weak inducer of apoptosis (TWEAK), interacting with Apo3, will induce apoptosis in some cells. Using Abs to TRAIL and an Apo3-IgG Fc fusion protein, we demonstrated that D10 cells express both TRAIL and TWEAK. The Apo3 fusion protein, but not human IgG, inhibited D10-induced macrophage apoptosis, as did anti-TRAIL. Further studies demonstrated that 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 TRAIL- and TWEAK-dependent pathways. Because normal T cells also express these molecules, these results support the concept that T cells have multiple pathways by which to induce macrophage apoptosis. These pathways may be important in immune processes such as macrophage homeostasis as well as in down-regulation of immune responses and elimination of macrophages infected with intracellular organisms.
人类骨髓每天产生约10¹⁰个单核细胞，这种产生必须通过相似的破坏速率来平衡。单核细胞/巨噬细胞在激活CD4⁺T细胞后可发生凋亡，提示这可能是有助于巨噬细胞稳态的一种机制。先前的报道表明Fas - Fas配体相互作用是介导这种反应的主要分子。然而，D10，一种Iak限制的克隆Th2细胞系，同样会在抗原呈递巨噬细胞中诱导凋亡，且D10细胞缺乏Fas配体。为证实D10细胞通过不依赖Fas的途径杀伤巨噬细胞，已表明D10细胞以抗原依赖的方式杀伤MRL lpr/lpr（Iak）巨噬细胞，提示存在其他机制。最近的报道显示，与Apo2相互作用的肿瘤坏死因子相关凋亡诱导配体（TRAIL）以及与Apo3相互作用的肿瘤坏死因子样凋亡弱诱导剂（TWEAK）可在某些细胞中诱导凋亡。使用抗TRAIL抗体和Apo3 - IgG Fc融合蛋白，我们证明D10细胞同时表达TRAIL和TWEAK。Apo3融合蛋白而非人IgG抑制了D10诱导的巨噬细胞凋亡，抗TRAIL抗体也有同样作用。进一步研究表明，克隆的Th1细胞系AE7和脾T细胞表达TWEAK、TRAIL和Fas配体，抑制这些分子也会抑制巨噬细胞杀伤。这些结果表明D10细胞通过依赖TRAIL和TWEAK的途径诱导巨噬细胞凋亡。由于正常T细胞也表达这些分子，这些结果支持T细胞有多种诱导巨噬细胞凋亡途径的概念。这些途径在诸如巨噬细胞稳态等免疫过程以及免疫反应的下调和清除感染细胞内病原体的巨噬细胞中可能很重要。
