CD27low Natural Killer Cells Prolong Allograft Survival in Mice by Controlling Alloreactive CD8+ T Cells in a T-Bet–Dependent Manner
CD27low Natural Killer Cells Prolong Allograft Survival in Mice by Controlling Alloreactive CD8+ T Cells in a T-Bet–Dependent Manner
复制标题
CD27low 自然杀伤细胞通过以 T-Betâ 依赖性方式控制同种异体反应性 CD8 T 细胞来延长小鼠同种异体移植物的存活率
DOI：
10.1097/tp.0000000000000585
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发表时间：
2015
期刊：
影响因子：
6.2
通讯作者：
Kroemer A
中科院分区：
文献类型：
--
作者：
Lantow M;Eggenhofer E;Sabet- Baktach M;Renner P;Rovira J;Koehl GE;Schlitt HJ;Geissler EK;Kroemer A
背景自然杀伤细胞（NK）在同种异体免疫反应中起着双重作用，因为它们既促进同种异体移植物存活，又促进排斥反应。本研究的目的是研究功能不同的NK细胞亚群在同种异体免疫中的作用，假设这种二分法是由不同NK细胞亚群的功能异质性解释的。我们使用缺乏成熟的CD 27低NK细胞的Rag−/− T-bet−/−小鼠，研究在共刺激阻断条件下T细胞介导的皮肤移植排斥模型中，CD 27低NK细胞与CD 27高NK细胞的不同作用。与Rag 1 −/− T-bet−/−小鼠（缺乏CD 27低NK细胞）相比，重建的Rag 1 −/−受体（具有CD 27低NK细胞）在共刺激阻断下显示出显著延长的同种异体移植物存活，表明CD 27低而非CD 27高NK细胞增强同种异体移植物存活。关键的是，Rag 1 −/− T-bet−/−受体表现出显著增加的同种异体反应性记忆CD 8 + T细胞应答，如增加的CD 8 + T细胞增殖和干扰素-γ产生所示。因此，我们推测，CD 27低NK细胞直接调节同种异体反应性CD 8 + T细胞反应的共刺激阻断条件下。为了测试这一点，我们过继转移CD 27低NK细胞到Rag 1 −/− T-bet−/−皮肤移植受体，发现CD 27低NK细胞通过抑制同种异体反应性干扰素-γ+ CD 8 + T细胞的增殖恢复更好的同种异体移植物存活率。
BackgroundNatural killer (NK) cells play a dichotomous role in alloimmune responses because they are known to promote both allograft survival and rejection. The aim of this study was to investigate the role of functionally distinct NK cell subsets in alloimmunity with the hypothesis that this dichotomy is explained by the functional heterogeneity of distinct NK cell subsets.MethodsBecause T-bet controls the maturation of NK cells from CD27 high to terminally differentiated CD27 low NK cells, we used Rag−/− T-bet−/− mice that lack mature CD27 low NK cells to study the distinct roles of CD27 low versus CD27 high NK cells in a model of T cell–mediated skin transplant rejection under costimulatory blockade conditions.ResultsWe found that T cell–reconstituted Rag1−/− recipients (possessing CD27 low NK cells) show significantly prolonged allograft survival on costimulatory blockade when compared to Rag1−/− T-bet−/− mice (lacking CD27 low NK cells), indicating that CD27 low but not CD27 high NK cells enhance allograft survival. Critically, Rag1−/− T-bet−/− recipients showed strikingly increased alloreactive memory CD8+ T cell responses, as indicated by increased CD8+ T cell proliferation and interferon-γ production. Therefore, we speculated that CD27 low NK cells directly regulate alloreactive CD8+ T cell responses under costimulatory blockade conditions. To test this, we adoptively transferred CD27 low NK cells into Rag1−/− T-bet−/− skin transplant recipients and found that the CD27 low NK cells restore better allograft survival by inhibiting the proliferation of alloreactive interferon-γ+ CD8+ T cells.ConclusionsIn summary, mature CD27 low NK cells promote allograft survival under costimulatory blockade conditions by regulating alloreactive memory CD8+ T-cell responses.