日本大阪大学Shiroh Iwanaga研究组开发出了疟疾感染红细胞上显示的RIFINs结合KIR2DL1和KIR2DS1。2025年6月11日出版的《自然》发表了这项成果。

在这里，课题组人员发现了一个RIFINs分支，它与抑制性免疫受体KIR2DL1的结合比KIR2DL1与人类配体（MHC I类）的结合更强。这种相互作用介导抑制性信号传导并抑制表达KIR2DL1的NK细胞的激活。研究团队发现KIR2DL1结合的RIFINs在非洲和亚洲的野外分离菌株中都很丰富，并揭示了这两种RIFINs如何与KIR2DL1结合。KIR2DL1的RIFIN结合面在同源激活免疫受体KIR2DS1中是保守的。研究人员发现结合KIR2DL1的RIFINs也可以结合KIR2DS1，从而激活表达KIR2DS1的NK细胞。本研究表明，激活杀伤性免疫球蛋白样受体可以招募NK细胞靶向病原体，并揭示了激活免疫受体在控制疟疾感染中的潜在作用。

研究人员表示，自然杀伤细胞（NK细胞）通过抑制和激活免疫受体来区分人类细胞和病原体。这些受体发出的信号决定NK细胞是否被激活并破坏靶细胞。在某些情况下，如杀伤性免疫球蛋白样受体，免疫受体是成对的，抑制性和激活性受体含有几乎相同的细胞外配体结合域，与不同的细胞内信号域偶联。先前的研究表明，在恶性疟原虫感染的红细胞表面显示的重复穿插家族（RIFIN）蛋白可以与抑制性免疫受体结合，抑制NK细胞的激活，减少寄生虫的杀伤。然而，没有病原体衍生的配体被确定为任何人类激活受体。

附：英文原文

Title: RIFINs displayed on malaria-infected erythrocytes bind KIR2DL1 and KIR2DS1

Author: Sakoguchi, Akihito, Chamberlain, Samuel G., Mrch, Alexander M., Widdess, Marcus, Harrison, Thomas E., Dustin, Michael L., Arase, Hisashi, Higgins, Matthew K., Iwanaga, Shiroh

Issue&Volume: 2025-06-11

Abstract: Natural killer (NK) cells use inhibitory and activating immune receptors to differentiate between human cells and pathogens. Signalling by these receptors determines whether an NK cell becomes activated and destroys a target cell. In some cases, such as killer immunoglobulin-like receptors, immune receptors are found in pairs, with inhibitory and activating receptors containing nearly identical extracellular ligand-binding domains coupled to different intracellular signalling domains1. Previous studies showed that repetitive interspersed family (RIFIN) proteins, displayed on the surfaces of Plasmodium falciparum-infected erythrocytes, can bind to inhibitory immune receptors and dampen NK cell activation2,3, reducing parasite killing. However, no pathogen-derived ligand has been identified for any human activating receptor. Here we identified a clade of RIFINs that bind to inhibitory immune receptor KIR2DL1 more strongly than KIR2DL1 binds to the human ligand (MHC class I). This interaction mediates inhibitory signalling and suppresses the activation of KIR2DL1-expressing NK cells. We show that KIR2DL1-binding RIFINs are abundant in field-isolated strains from both Africa and Asia and reveal how the two RIFINs bind to KIR2DL1. The RIFIN binding surface of KIR2DL1 is conserved in the cognate activating immune receptor KIR2DS1. We find that KIR2DL1-binding RIFINs can also bind to KIR2DS1, resulting in the activation of KIR2DS1-expressing NK cells. This study demonstrates that activating killer immunoglobulin-like receptors can recruit NK cells to target a pathogen and reveals a potential role for activating immune receptors in controlling malaria infection.

DOI: 10.1038/s41586-025-09091-y

Source: https://www.nature.com/articles/s41586-025-09091-y