The KIR family contains both inhibitory and activating receptors, which have largely conserved extracellular domains. Inspection of the RBK21–KIR2DL1 structure showed that the KIR2DL1 residues, which interact with RBK21, were almost completely conserved in KIR2DS1 (Fig. 4a,b), except for the conservative substitution of V111L. Therefore, we used SPR analysis to quantify the binding of KIR2DL1 and KIR2DS1 to RBK21 and the MHC class I molecule (HLA-Cw4). KIR2DS1 bound with a 1.7 μM affinity to RBK21, close to the 0.5 µM affinity of the RBK21–KIR2DL1 complex, whereas its affinity for HLA-Cw4 is more than 10-fold weaker (Fig. 4c). We also measured the binding of the Kenyan and Senegalese field isolates to KIR2DS1 and found that all KIR2DL1-binding RIFINs also bound to KIR2DS1 with low micromolar affinities (Extended Data Fig. 7a). Flow cytometry analysis demonstrated that transgenic parasites expressing RBK21 also bound to KIR2DS1 (Fig. 4d). This indicates that KIR2DL1-binding RIFINs are new pathogen-displayed ligands for activating KIR receptors, supporting a model in which RIFIN recognition might activate KIR2DS1-expressing NK cells to destroy infected erythrocytes.
Fig. 4: KIR2DL1-binding RIFINs also bind and signal through activating immune receptor KIR2DS1.
a, Sequence alignment of the regions of KIR2DL1 and KIR2DS1, which bind RBK21 and HLA-Cw4. Residues interacting with RBK21 (pink) and HLA-Cw4 (orange) are highlighted. *Indicates identical residues, : indicates similar residues and . indicates residues of weakly similar properties. b, The structure of KIR2DL1 (green) overlaid with a homology model of KIR2DS1 (blue). Residues that contact RBK21 (pink surface) or HLA-Cw4 (orange surface) are shown as sticks. Polymorphisms at positions 91 and 111 are highlighted. c, SPR analysis of the binding of KIR2DL1 and KIR2DS1 to RBK21 and HLA-Cw4. Each point represents the mean of three independent measurements, and the error bars represent the s.d. Dissociation constants, shown above the graph, were calculated using ‘one-site total’ fitting model in Prism 10, including all three measurements in fitting. d, Normalized MFI of binding of iRBC, expressing chimaeric RBK21 (cRBK21) and full-length RBK21 (fRBK21), to KIR2DS1-Fc was calculated by dividing by the MFI of 3D7. Data represent the mean ± s.d. of three biologically independent samples, with ****P 0.0001 (two-sided Student’s t-test). e, GFP expression in KIR2DS1-reporter cells upon stimulation with P. falciparum 3D7 (left) or with a transgenic parasite expressing RBK21 (right). The percentage of GFP-positive cells is shown. f, KIR2DS1-positive NK cells were gated, as indicated in the box. g–i, Effect of RBK21 on CD107a expression (g) and IFNγ (h) and TNF (i) production in the gated KIR2DS1+ subset from f, assessed as shown in Fig. 3c–e. The 3D7 strain and iRBC expressing PF3D7_1254200 (ctl-RIFIN) were used as negative controls. Data represent the mean (n = 9 independent measurements from one donor) with ****P 0.0001 (two-sided Student’s t-test). A similar assay using a different donor is shown in Extended Data Fig. 7c. Exact P values in source data.
Source Data
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Using the NFAT–GFP reporter system modified to express KIR2DS1, we next examined whether binding of RBK21 to KIR2DS1 resulted in signal transduction (Fig. 4e). Increased expression of GFP was found in KIR2DS1-expressing reporter cells co-cultured with RBK21-expressing parasites (31.9%) compared to the control (0.4%). We also co-cultured RBCs infected with RBK21-expressing transgenic parasites with primary NK cells containing the KIR2DS1-positive NK subset, which was obtained from a donor by flow sorting (Fig. 4f), and monitored the markers CD107a, TNF and IFNγ. The presence of RBK21 resulted in increased CD107a expression (82.1 ± 1.1%) and in the production of IFNγ (29.4 ± 1.5%) and TNF (27.8 ± 0.8%) in the KIR2DS1-positive NK cell subset (Fig. 4f–i and Extended Data Fig. 8a). By contrast, RBCs infected with wild-type parasite (CD107a, 11.2 ± 0.6%; IFNγ, 1.7 ± 0.2%; and TNF, 1.5 ± 0.4%) or with a transgenic parasite expressing PF3D7_1254200 (CD107a, 11.2 ± 0.7%; IFNγ, 0.9 ± 0.1%; and TNF, 0.9 ± 0.2%) did not activate the KIR2DS1-expressing NK subset. Similar RBK21-induced increases in CD107a expression (90.1 ± 0.3%) and in production of IFNγ (61.1 ± 1.4%) and TNF (48.9 ± 1.1%) were also observed in the KIR2DS1-positive NK subset obtained from a second donor (Extended Data Figs. 7b and 8b). Although activation of KIR2DS1-positive NK subset by RBCs infected with wild-type parasite (CD107a, 68.6 ± 0.8%; IFNγ, 30.9 ± 0.8%; and TNF, 17.4 ± 0.4%) or with a transgenic parasite expressing PF3D7_1254200 (CD107a, 71.2 ± 0.3%; IFNγ, 29.1 ± 0.4%; and TNF, 15.4 ± 0.4%) was detected, the activation by iRBC with RBK21 was significantly greater than either (Extended Data Fig. 7b). Therefore, KIR2DL1-binding RIFIN can engage both the inhibitory receptor KIR2DL1 and activating receptor KIR2DS1. Although the engagement of KIR2DL1 suppresses KIR2DL1-expressing NK cells, KIR2DS1 binding has the opposite effect, activating KIR2DS1-expressing NK cells by triggering both cytotoxic and cytokine responses. Because different NK cells present within different humans express different KIRs, this will equip the subset of NK cells expressing KIR2DS1 with the ability to clear iRBCs expressing these RIFINs.
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Sakoguchi, A., Chamberlain, S.G., Mørch, A.M. et al. RIFINs displayed on malaria-infected erythrocytes bind KIR2DL1 and KIR2DS1.
Nature (2025).
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Sakoguchi, A., Chamberlain, S.G., Mørch, A.M. et al. RIFINs displayed on malaria-infected erythrocytes bind KIR2DL1 and KIR2DS1.
Nature (2025). https://doi.org/10.1038/s41586-025-09091-y
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Tags: erythrocyte destruction by NK cellsfield isolates binding studiesflow cytometry in malaria researchimmune receptor signalingKIR family receptorsKIR2DL1 and KIR2DS1 bindingmalaria-infected erythrocytesMHC class I interactionNK cell activation mechanismsRBK21 affinity analysisRIFINs as ligandstransgenic parasites
