TGF-β-dependent CD103 expression by CD8+ T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease
TGF-β-dependent CD103 expression by CD8+ T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease
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DOI：
10.1084/jem.20041044
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发表时间：
2005-05-16
影响因子：
15.3
通讯作者：
Hadley, GA
中科院分区：
文献类型：
--
作者：
El-Asady, R;Yuan, RW;Hadley, GA
供体效应T细胞群对宿主肠上皮的破坏是移植物抗宿主病（GVHD）的标志，但其潜在机制仍不清楚。我们证明，表达CD103的CD8（+）T细胞，一种赋予上皮配体E-cadherin特异性的整合素，在这一过程中起着关键作用。TCR转基因GVHD模型用于证明CD103由在GVHD期间在宿主肠上皮中积累的宿主特异性CD8（+）T细胞效应物群体（CD8效应物）选择性表达。虽然宿主特异性CD8效应物浸润了广泛的宿主区室，但只有那些浸润肠上皮的效应物表达CD103。宿主特异性CD8效应子表达TGF-β显性阴性II型受体，在进入肠上皮时CD103表达有缺陷，这表明局部TGF-β活性是关键调节因子。宿主特异性CD103表达缺陷的CD8效应子成功迁移到宿主肠上皮，但保留在该位点的效率远低于野生型宿主特异性CD8效应子。这些事件与GVHD发病机制的相关性得到了以下发现的支持，即CD103缺陷型CD8（+）T细胞在转移肠道GVHD病理和死亡率方面存在显著缺陷。总的来说，这些数据证明了TGF-β依赖性CD103表达在决定GVHD发病过程中CD8（+）T细胞的肠道向性和破坏潜力方面的关键作用。
Destruction of the host intestinal epithelium by donor effector T cell populations is a hallmark of graft-versus-host disease (GVHD), but the underlying mechanisms remain obscure. We demonstrate that CD8(+) T cells expressing CD103, an integrin conferring specificity for the epithelial ligand E-cadherin, play a critical role in this process. A TCR transgenic GVHD model was used to demonstrate that CD103 is selectively expressed by host-specific CD8(+) T cell effector populations (CD8 effectors) that accumulate in the host intestinal epithelium during GVHD. Although host-specific CD8 effectors infiltrated a wide range of host compartments, only those infiltrating the intestinal epithelium expressed CD103. Host-specific CD8 effectors expressing a TGF-beta dominant negative type II receptor were defective in CD103 expression on entry into the intestinal epithelium, which indicates local TGF-beta activity as a critical regulating factor. Host-specific CD8 effectors deficient in CD103 expression successfully migrated into the host intestinal epithelium but were retained at this site much less efficiently than wild-type host-specific CD8 effectors. The relevance of these events to GVHD pathogenesis is supported by the finding that CD103-deficient CD8 (+) T cells were strikingly defective in transferring intestinal GVHD pathology and mortality. Collectively, these data document a pivotal role for TGF-beta-dependent CD103 expression in dictating the gut tropism, and hence the destructive potential, of CD8(+) T cells during GVHD pathogenesis.