Cytokine Complex-expanded Natural Killer Cells Improve Allogeneic Lung Transplant Function via Depletion of Donor Dendritic Cells
Cytokine Complex-expanded Natural Killer Cells Improve Allogeneic Lung Transplant Function via Depletion of Donor Dendritic Cells
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DOI：
10.1164/rccm.201209-1749oc
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发表时间：
2013-06-15
影响因子：
24.7
通讯作者：
Muenz, Christian
中科院分区：
文献类型：
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作者：
Jungraithmayr, Wolfgang;Codarri, Laura;Muenz, Christian
原理：自然杀伤（NK）细胞是靶向病毒感染细胞和肿瘤细胞的先天性淋巴细胞。关于它们限制适应性免疫应答的能力知之甚少。目的：因此，我们研究NK细胞在多大程度上影响小鼠肺同种异体移植物排斥反应。方法：为此，我们采用小鼠原位肺移植模型。测量和主要结果：我们在此证明NK细胞在T细胞之前浸润小鼠同种异体肺移植物，从而减少同种异体移植物炎症，NK细胞缺乏会增强同种异体移植排斥反应。相比之下，通过IL-15/IL-15 R α复合物处理的受体NK细胞扩增导致T细胞浸润减少和同种异体反应性T细胞引发以及同种异体肺移植功能改善。只有有穿孔素活性的NK细胞能够将这些有益作用转移到移植的NK细胞缺陷型IL-15 R α（-/-）小鼠中，而穿孔素缺陷型NK细胞则不能。这些NK细胞在体外杀死同种异体树突状细胞（DCs），并显着减少同种异体DCs在体内移植肺的数量。此外，DC耗尽的肺同种异体移植物呈现减少的迹象reject.Conclusions：这些结果表明，NK细胞有利于移植物接受耗尽供体来源的DC，否则将引发同种异体反应性T细胞反应。因此，应在临床上探索增强NK细胞反应性的预处理方案，以准备肺移植受体。
Rationale: Natural killer (NK) cells are innate lymphocytes that target virus-infected and tumor cells. Much less is known about their ability to limit adaptive immune responses.Objectives: Thus, we investigated to what extent NK cells can influence mouse lung allograft rejection.Methods: For this purpose, we employed an orthotopic lung transplantation model in mice.Measurements and Main Results: We demonstrate here that NK cells infiltrate mouse lung allografts before T cells and thereby diminished allograft inflammation, and that NK-cell deficiency enhanced allograft rejection. In contrast, expansion of recipient NK cells through IL-15/IL-15R alpha complex treatment resulted in decreased T-cell infiltration and alloreactive T-cell priming as well as improved function of the allogeneic lung transplant. Only perforin-competent, but not perforin-deficient, NK cells were able to transfer these beneficial effects into transplanted NK cell-deficient IL-15R alpha(-/-) mice. These NK cells killed allogeneic dendritic cells (DCs) in vitro and significantly decreased the number of allogeneic DCs in transplanted lungs in vivo. Furthermore, DC-depleted lung allografts presented decreased signs of rejection.Conclusions: These results suggest that NK cells favor allograft acceptance by depleting donor-derived DCs, which otherwise would prime alloreactive T-cell responses. Thus, conditioning regimens that augment NK-cell reactivity should be clinically explored to prepare lung allograft recipients.