Identification of RIFIN binding to KIR receptor from RIFIN expression library of Plasmodium flaicparum.
To discriminate between our own cells and those of a pathogen, natural killer cells are armed with inhibitory and activating immune receptors. The balance in signalling mediated by these receptors determines whether an NK cell is activated to destroy a target cell. In some cases, such as the KIRs, 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 have shown that RIFINs, displayed on 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 activating receptor. Here, we identify a clade of RIFINs that bind to inhibitory immune receptor KIR2DL1 more strongly than KIR2DL1 binds the human ligand, MHC class I. We demonstrate that this interaction mediates inhibitory signaling 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 two RIFINs bind KIR2DL1. We also demonstrate that 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 activation of KIR2DS1-expressing NK cells. This study demonstrates for the first time that activating KIRs can recruit natural killer cells to target a pathogen and reveals a potential role for activating immune receptors in control of malaria infection Overall design: Amplicon-seq for KIR2DL1-binding RIFIN recovered from sorted infected RBC from RIFIN expression library.