The SIRPα-CD47 immune checkpoint in NK cells.
The SIRPα-CD47 immune checkpoint in NK cells.
复制标题
NK细胞中SIRPα-CD47免疫检查点的研究。
DOI：
10.1084/jem.20200839
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发表时间：
2021-03-01
期刊：
影响因子：
--
通讯作者：
Schrepfer S
中科院分区：
文献类型：
--
作者：
Deuse T;Hu X;Agbor-Enoh S;Jang MK;Alawi M;Saygi C;Gravina A;Tediashvili G;Nguyen VQ;Liu Y;Valantine H;Lanier LL;Schrepfer S
NK细胞能够上调SIRPα， SIRPα在CD47接合时传递强烈的抑制信号。这种免疫检查点的调节可以产生通用的异体再生细胞产物或增强NK细胞介导的肿瘤细胞杀伤。在这里，我们报告了NK细胞中免疫检查点信号调节蛋白α (SIRPα)的存在和功能，并描述了如何调节它以进行细胞治疗。NK细胞SIRPα在IL-2刺激下上调，以阈值依赖的方式与靶细胞CD47相互作用，并对抗其他刺激信号，包括IL-2、CD16或NKG2D。CD47的表达升高可以保护K562肿瘤细胞、小鼠和人MHC i类缺陷靶细胞对抗SIRPα+原代NK细胞，但对SIRPα−NKL或NK92细胞不起作用。SIRPα缺乏或抗体阻断可增加NK细胞的杀伤能力。在异种环境下，恒河猴CD47在人mhc缺陷细胞中的过表达可防止恒河猴NK细胞的细胞毒性。SIRPα-CD47轴具有高度的物种特异性。总之，结果表明SIRPα-CD47免疫检查点的破坏可能会增强NK细胞的抗肿瘤反应，CD47表达的升高可能会阻止NK细胞介导的同种异体和异种组织的杀伤。
NK cells are able to upregulate SIRPα, which transmits a strong inhibitory signal upon CD47 engagement. Modulation of this immune checkpoint can enable the generation of universal allogeneic regenerative cell products or enhance NK cell–mediated tumor cell killing. Here we report on the existence and functionality of the immune checkpoint signal regulatory protein α (SIRPα) in NK cells and describe how it can be modulated for cell therapy. NK cell SIRPα is up-regulated upon IL-2 stimulation, interacts with target cell CD47 in a threshold-dependent manner, and counters other stimulatory signals, including IL-2, CD16, or NKG2D. Elevated expression of CD47 protected K562 tumor cells and mouse and human MHC class I–deficient target cells against SIRPα+ primary NK cells, but not against SIRPα− NKL or NK92 cells. SIRPα deficiency or antibody blockade increased the killing capacity of NK cells. Overexpression of rhesus monkey CD47 in human MHC-deficient cells prevented cytotoxicity by rhesus NK cells in a xenogeneic setting. The SIRPα–CD47 axis was found to be highly species specific. Together, the results demonstrate that disruption of the SIRPα–CD47 immune checkpoint may augment NK cell antitumor responses and that elevated expression of CD47 may prevent NK cell–mediated killing of allogeneic and xenogeneic tissues.
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