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SHUTTERSTOCK
‘Natural killer’ (NK) cells, a key component of the immune system, patrol the body to identify and destroy infected or abnormal cells. These cells rely on a balance of activating and inhibitory receptors to determine whether a cell is friend or foe. When these natural killer cells encounter a pathogen, activating receptors trigger a lethal response, while inhibitory receptors prevent attacks on the body’s own cells.
The malaria parasite Plasmodium falciparum, responsible for the deadliest form of the disease, has evolved a cunning strategy to escape detection. It disguises infected red blood cells with a diverse family of proteins known as RIFINs, originally discovered at Oxford University. Some RIFINs bind to inhibitory receptors like LILRB1 on natural killer cells, effectively disarming them.
The latest study, published in Nature, is a collaboration between scientists from the Kennedy Institute, Osaka University, and the Department of Biochemistry at Oxford. Akihito Sakoguchi, Shiroh Iwanaga, and Hisashi Arase from Osaka—identified a new subset of RIFINs that bind to another inhibitory receptor, or “killer immunoglobulin-like receptors”, called
KIR2DL1. Structural studies led by Sam Chamberlain at the Biochemistry Department then revealed how these RIFINs interact with KIRs, and further studies with Alex Mørch, Marcus Widdess and Prof Michael Dustin from the Kennedy Institute demonstrated that this interaction suppresses natural killer cell activity.
However, the team made a surprising discovery: the same RIFINs that bind to the inhibitory receptor KIR2DL1 also bind to its activating counterpart, KIR2DS1. These paired receptors share similar structures but trigger opposite responses. When natural killer cells express KIR2DS1, binding to the RIFINs activates the cells, prompting them to kill the infected red blood cells.
Michael Dustin, Kennedy Trust Professor of Molecular Immunology said: ‘Our immune can turn the tables on malaria.'
‘This suggests that KIR2DS1 may have evolved specifically to counteract the malaria parasite’s evasion tactics,’ said Sam Chamberlain.
With many hundreds of RIFINs still with unknown function, the researchers believe this discovery is just the beginning. ‘Each new RIFIN we study could reveal more about how our immune system has adapted to fight this ancient and deadly foe,’ Matt Higgins added.
The full study, titled “RIFINs displayed on malaria-infected erythrocytes bind both KIR2DL1 and KIR2DS1”, is available in Nature online and in print on 31 July 2025.