Concomitant deletion of SLAM-family receptors, NKG2D and DNAM-1 reveals gene redundancy of NK cell activating receptors in NK cell development and education
Concomitant deletion of SLAM-family receptors, NKG2D and DNAM-1 reveals gene redundancy of NK cell activating receptors in NK cell development and education
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SLAM家族受体、NKG2D和DNAM-1的同时删除揭示了NK细胞发育和教育中NK细胞激活受体的基因冗余
DOI：
10.1002/jlb.1ma1019-186r
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发表时间：
2019-11-15
影响因子：
5.5
通讯作者：
Dong, Zhongjun
中科院分区：
文献类型：
--
作者：
Chen, Shasha;Dong, Zhongjun
NK细胞使用多种种系编码的活化受体识别“不需要的”细胞，例如信号淋巴细胞活化分子（SLAM）家族受体（SFR）的七个成员、自然杀伤细胞组2D（NKG 2D）和DNAX辅助分子-1（DNAM-1）。这些受体是否冗余或协同调节NK细胞发育和效应器功能仍然知之甚少。通过分别或联合产生缺乏SFR、NKG 2D和DNAM-1的小鼠，我们发现SFR成员之一的SLAMF 6与NK细胞分化相关，但其缺失对NK细胞分化和功能没有严重影响，可能是由于SFR冗余。此外，我们发现SFR可能与其他NK细胞活化受体一起调节NK细胞的发育和功能。我们发现，SFR缺乏导致未成熟NK细胞亚群（CD 27（+）CD 11b（-））增加，并且这种效应进一步被NKG 2D而不是DNAM-1的额外缺乏所增强。然而，SFR缺陷的NK细胞表现出对“缺失自身”造血靶点的反应性升高，而NKG 2D或DNAM-1的缺失可以部分消除SFR缺陷对NK细胞活化的升高作用。因此，我们的研究结果揭示了活化受体在调节NK细胞分化和活化中的复杂性，扩展了我们对NK细胞活化受体的基因冗余和补偿作用的认识。
NK cells recognize "unwanted" cells using a variety of germline-encoded activating receptors, such as the seven members of signaling lymphocyte activating molecule (SLAM)-family receptors (SFRs), natural killer cell group 2D (NKG2D), and DNAX accessory molecule-1(DNAM-1). Whether these receptors redundantly or synergistically regulate NK cell development and effector function remains poorly understood. By generating mice lacking SFRs, NKG2D, and DNAM-1, separately or in combination, we found that SLAMF6, one of the SFR members, was associated with NK cell differentiation, but its absence had no severe effect on NK cell differentiation and function, likely due to SFR redundancy. Moreover, we revealed that SFRs might work with other NK cell activating receptors in regulating NK cell development and function. We found that SFR deficiency caused an increase in immature NK cell subsets (CD27(+)CD11b(-)), and this effect was further augmented by the additional deficiency of NKG2D but not DNAM-1. However, SFR-deficient NK cells exhibited elevated responsiveness against "missing-self" hematopoietic targets, whereas the deletion of either NKG2D or DNAM-1 could partially abrogate the elevated effect of SFR deficiency on NK cell activation. Therefore, our results reveal the complexity of activating receptors in regulating NK cell differentiation and activation, extending our insights into the gene redundancy and compensatory effect of NK cell activating receptors.