An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues.
An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues.
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DOI：
10.1084/jem.20060376
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发表时间：
2006-08-07
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将T细胞转移至新照射的同种异体受者体内会导致它们迅速募集到非淋巴组织，在那里它们会诱发移植物抗宿主病（GVHD）。相反，当供体T细胞被转移至已建立的混合嵌合体（MCs）中时，尽管存在强烈的移植物抗宿主（GVH）反应，该反应会清除正常及恶性的宿主造血细胞，但不会诱发GVHD。我们在此证明，转移至混合嵌合体或新照射小鼠体内的供体GVH反应性T细胞会经历相似的扩增和激活，进入非淋巴组织所需的归巢分子也有相似的上调。通过动态双光子体内显微镜技术，我们发现这些活化的T细胞不会进入已建立的混合嵌合体中的GVHD靶组织，这与活化的T细胞必然迁移至非淋巴组织的传统观点相悖。相反，我们表明非淋巴组织内存在炎症是活化的T细胞迁移至该部位的先决条件。我们的研究有助于解释这一矛盾现象，即GVH反应性T细胞能够介导移植物抗白血病反应，而在已建立的混合嵌合体中不诱发GVHD。
Transfer of T cells to freshly irradiated allogeneic recipients leads to their rapid recruitment to nonlymphoid tissues, where they induce graft-versus-host disease (GVHD). In contrast, when donor T cells are transferred to established mixed chimeras (MCs), GVHD is not induced despite a robust graft-versus-host (GVH) reaction that eliminates normal and malignant host hematopoietic cells. We demonstrate here that donor GVH-reactive T cells transferred to MCs or freshly irradiated mice undergo similar expansion and activation, with similar up-regulation of homing molecules required for entry to nonlymphoid tissues. Using dynamic two-photon in vivo microscopy, we show that these activated T cells do not enter GVHD target tissues in established MCs, contrary to the dogma that activated T cells inevitably traffic to nonlymphoid tissues. Instead, we show that the presence of inflammation within a nonlymphoid tissue is a prerequisite for the trafficking of activated T cells to that site. Our studies help to explain the paradox whereby GVH-reactive T cells can mediate graft-versus-leukemia responses without inducing GVHD in established MCs.