澳大利亚莫纳什大学Nicholas D. Huntington研究小组发现，IKAROS和AIOLOS直接调控AP-1转录复合物并对NK细胞的发育至关重要。2024年1月5日，《自然—免疫学》杂志在线发表了这项成果。

通过条件性基因失活，研究人员发现Ikzf1/Ikaros对正常的自然杀伤（NK）细胞淋巴细胞生成至关重要，IKZF1直接抑制白细胞介素-15受体的负调控因子Cish，导致白细胞介素-15受体信号转导受损。在Ikzf1缺失的NK细胞中，Bcl2l11和BIM的水平以及内在凋亡都有所增加，这也是NK淋巴细胞减少症的部分原因，因为当Ikzf1和Bcl2l11被共同删除时，两者都恢复到了正常水平。

Ikzf1无效的NK细胞出现了广泛的转录改变，AP-1转录复合物表达减少，Ikzf2/Helios和Ikzf3/Aiolos表达增加。IKZF1和IKZF3直接与AP-1家族成员结合，在NK细胞中缺失Ikzf1和Ikzf3会导致Jun/Fos表达进一步减少，外周NK细胞完全丧失。总之，研究人员发现Ikaros家族成员是细胞凋亡、细胞因子反应性和AP-1转录活性的重要调节因子。

研究人员表示，Ikaros转录因子对适应性淋巴细胞的功能至关重要，但它们在先天性淋巴细胞形成中的作用尚不清楚。

附：英文原文

Title: IKAROS and AIOLOS directly regulate AP-1 transcriptional complexes and are essential for NK cell development

Author: Goh, Wilford, Sudholz, Harrison, Foroutan, Momeneh, Scheer, Sebastian, Pfefferle, Aline, Delconte, Rebecca B., Meng, Xiangpeng, Shen, Zihan, Hennessey, Robert, Kong, Isabella Y., Schuster, Iona S., Andoniou, Christopher E., Davis, Melissa J., Hediyeh-Zadeh, Soroor, Souza-Fonseca-Guimaraes, Fernando, Parish, Ian A., Beavis, Paul, Thiele, Daniel, Chopin, Michael, Degli-Esposti, Mariapia A., Cursons, Joe, Kallies, Axel, Rautela, Jai, Nutt, Stephen L., Huntington, Nicholas D.

Issue&Volume: 2024-01-05

Abstract: Ikaros transcription factors are essential for adaptive lymphocyte function, yet their role in innate lymphopoiesis is unknown. Using conditional genetic inactivation, we show that Ikzf1/Ikaros is essential for normal natural killer (NK) cell lymphopoiesis and IKZF1 directly represses Cish, a negative regulator of interleukin-15 receptor resulting in impaired interleukin-15 receptor signaling. Both Bcl2l11 and BIM levels, and intrinsic apoptosis were increased in Ikzf1-null NK cells, which in part accounts for NK lymphopenia as both were restored to normal levels when Ikzf1 and Bcl2l11 were co-deleted. Ikzf1-null NK cells presented extensive transcriptional alterations with reduced AP-1 transcriptional complex expression and increased expression of Ikzf2/Helios and Ikzf3/Aiolos. IKZF1 and IKZF3 directly bound AP-1 family members and deletion of both Ikzf1 and Ikzf3 in NK cells resulted in further reductions in Jun/Fos expression and complete loss of peripheral NK cells. Collectively, we show that Ikaros family members are important regulators of apoptosis, cytokine responsiveness and AP-1 transcriptional activity.

DOI: 10.1038/s41590-023-01718-4

Source: https://www.nature.com/articles/s41590-023-01718-4