The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease
The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease
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DOI：
10.1172/jci39395
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发表时间：
2010-01-01
影响因子：
15.9
通讯作者：
van den Brink, Marcel R. M.
中科院分区：
文献类型：
--
作者：
Na, Il-Kang;Lu, Sydney X.;van den Brink, Marcel R. M.
胸腺移植物抗宿主病 (tGVHD) 可导致同种异体骨髓移植 (allo-BMT) 后严重的 T 细胞缺乏和功能限制。然而，tGVHD 的细胞机制以及供体同种异体反应性 T 细胞与胸腺组织之间的相互作用仍不清楚。使用临床相关的小鼠同种异体 BMT 模型，我们在此表明，即使是极少量的供体同种异体反应性 T 细胞，引起轻度非致命性系统性移植物抗宿主病，足以损害胸腺、延迟 T 谱系重建并损害供体外周 T 细胞功能。此外，为了介导 tGVHD，供体同种异体反应性 T 细胞需要运输分子，包括 CCR9、L 选择素、P 选择素糖蛋白配体-1、整合素亚基 α(E) 和 β(7)、CCR2 和 CXCR3，以及共刺激/抑制分子，包括 Ox40 和癌胚抗原相关细胞 粘附分子 1。我们发现 BMT 预处理方案中的辐射上调了胸腺基质细胞（尤其是上皮细胞）上死亡受体 Fas 和死亡受体 5 (DR5) 的表达，同时降低了抗凋亡调节细胞 caspase-8 样抑制蛋白的表达。供体同种反应性 T 细胞使用同源蛋白 FasL 和 TNF 相关凋亡诱导配体 (TRAIL)（但不是 TNF 或穿孔素）来介导 tGVHD，从而损害胸腺基质细胞、细胞结构和功能。因此，干扰 Fas/FasL 和 TRAIL/DR5 相互作用的策略可能是减轻同种异体 BMT 受体中 tGVHD 和改善 T 细胞重建的一种方法。
Thymic graft-versus-host disease (tGVHD) can contribute to profound T cell deficiency and repertoire restriction after allogeneic BM transplantation (allo-BMT). However, the cellular mechanisms of tGVHD and interactions between donor alloreactive T cells and thymic tissues remain poorly defined. Using clinically relevant murine allo-BMT models, we show here that even minimal numbers of donor alloreactive T cells, which. caused mild nonlethal systemic graft-versus-host disease, were sufficient to damage the thymus, delay T lineage reconstitution, and compromise donor peripheral T cell function. Furthermore, to mediate tGVHD, donor alloreactive T cells required trafficking molecules, including CCR9, L selectin, P selectin glycoprotein ligand-1, the integrin subunits alpha(E) and beta(7), CCR2, and CXCR3, and costimulatory/inhibitory molecules, including Ox40 and carcinoembryonic antigen-associated cell adhesion molecule 1. We found that radiation in BMT conditioning regimens upregulated expression of the death receptors Fas and death receptor 5 (DR5) on thymic stromal cells (especially epithelium), while decreasing expression of the antiapoptotic regulator cellular caspase-8-like inhibitory protein. Donor alloreactive T cells used the cognate proteins FasL and TNF-related apoptosis-inducing ligand (TRAIL) (but not TNF or perforin) to mediate tGVHD, thereby damaging thymic stromal cells, cytoarchitecture, and function. Strategies that interfere with Fas/FasL and TRAIL/DR5 interactions may therefore represent a means to attenuate tGVHD and improve T cell reconstitution in allo-BMT recipients.