RIFINs displayed on malaria-infected erythrocytes bind both KIR2DL1 and KIR2DS1

Abstract To discriminate between our own cells and foreign cells such as a pathogen, natural killer cells are armed with inhibitory and activating immune receptors. In some cases, such as the KIRs, these are found in pairs, with inhibitory and activating receptors containing nearly identical extracellular domains that are coupled to different intracellular signalling domains 1 . The balance in signalling mediated by these receptors determines whether an NK cell is activated to destroy a target cell. Previous studies have shown that RIFINs, displayed on surfaces of Plasmodium falciparum -infected erythrocytes, can bind to inhibitory immune receptors and dampen NK cell activation 2,3 , reducing parasite killing. Here, we identify a clade of RIFINs that bind to inhibitory immune receptor KIR2DL1 approximately ten-times more strongly than KIR2DL1 binds its host ligand, MHC class I. We show that this interaction mediates inhibitory signalling and reduces activation of KIR2DL1-expressing NK cells. We reveal the structural basis for KIR2DL1 binding and show that the RIFIN binding surface of KIR2DL1 is conserved in the activating immune receptor KIR2DS1. We find that KIR2DL1-binding RIFINs can also bind to KIR2DS1 and that these RIFINs cause activation of KIR2DS1-expressing NK cells. This highlights the evolutionary battle between pathogen and host, suggesting that activating KIRs may have evolved to allow detection of red blood cells infected with Plasmodium falciparum , helping the host to clear the parasite.