Natural killer cells recruited into lymph nodes inhibit alloreactive T-cell activation through perforin-mediated killing of donor allogeneic dendritic cells
Natural killer cells recruited into lymph nodes inhibit alloreactive T-cell activation through perforin-mediated killing of donor allogeneic dendritic cells
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DOI：
10.1182/blood-2007-10-120089
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发表时间：
2008-08-01
期刊：
影响因子：
20.3
通讯作者：
Guery, Jean-Charles
中科院分区：
文献类型：
--
作者：
Laffont, Sophie;Seillet, Cyril;Guery, Jean-Charles
在骨髓移植中利用自然杀伤 (NK) 细胞同种异体反应性来改善临床结果。同样，在实体器官移植中，最近的研究表明，受体 NK 细胞可以通过其阻止移植物来源的同种异体树突细胞 (DC) 持续存在的能力来限制同种异体反应性 T 细胞反应。在 CD4+ T 细胞介导的同种异体皮肤移植排斥模型中，我们发现宿主 NK 细胞同种异体反应性缺失的特点是同种异体反应性效应 T 淋巴细胞（包括 Th2 细胞）的扩增增强，以及排斥组织中大量嗜酸性粒细胞浸润。在注射同种异体 BALB/c (H-2d) DC 的 CD8+ T 细胞缺陷型 C57BL/6 (H-2b) 受体中，我们证明表达 H-2Dd 特异性 Ly49D 激活受体的 NK 细胞参与同种异体反应性 CD4+ T 细胞反应的调节。此外，我们发现 Ly49D+ CD127NK 细胞在 DC 引流淋巴结内被募集，并通过穿孔素途径快速消除同种异体 H-2d DC。在正常小鼠中，我们进一步证明 NK 细胞通过快速消除同种异体 DC 强烈抑制同种异体 CD8+ T 细胞反应。因此，NK 细胞通过其杀死引流淋巴结中同种异体 DC 的能力，充当同种异体移植中同种异体反应性 T 细胞启动的早期调节者。
Natural killer (NK)-cell alloreactivity is exploited in bone marrow transplantation to improve clinical outcome. Likewise, in solid organ transplantation, it has been recently shown that recipient NK cells may limit alloreactive T-cell responses through their capacity to prevent the persistence of graft-derived allogeneic dendritic cells (DCs). In a model of CD4+ T cell-mediated allogeneic skin graft rejection, we show that the absence of host NK-cell alloreactivity was characterized by enhanced expansion of alloreactive effector T lymphocytes, including Th2 cells, and massive eosinophilic infiltrates in the rejected tissues. In CD8+ T celldeficient C57BL/6 (H-2b) recipients injected with allogeneic BALB/c (H-2d) DCs, we demonstrated that NK cells expressing the H-2Dd-specific Ly49D activating receptor were implicated in the regulation of alloreactive CD4+ T-cell responses. Moreover, we showed that Ly49D+ CD127NK cells were recruited within DC drain- ing lymph nodes and rapidly eliminated allogeneic H-2d DCs through the perforin pathway. In normal mice, we further demonstrated that NK cells by quickly eliminating allogeneic DCs strongly inhibited alloreactive CD8+ T-cell responses. Thus, NK cells act as early regulators of alloreactive T-cell priming in allotransplantation through their capacity to kill allogeneic DCs in draining lymph nodes.