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Identification of RIFIN binding to KIR receptor from RIFIN expression library of Plasmodium flaicparum.

ABSTRACT: 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

ORGANISM(S): Plasmodium falciparum

PROVIDER: GSE286478 | GEO | 2025/01/15

REPOSITORIES: GEO

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Project description:Dozens of transplants generated from pluripotent stem cells are currently in clinical trials. The creation of patient-specific iPSCs makes personalized therapy possible due to their main advantage of immunotolerance. However, some reports have claimed recently that aberrant gene expression followed by proteome alterations and neoantigen formation can result in iPSCs recognition by autologous T-cells. Meanwhile, the possibility of NK-cell activation has not been previously considered. This study focused on the comparison of autologous and allogeneic immune response to iPSC-derived cells and isogeneic parental somatic cells used for reprogramming. Here we report that cells differentiated from iPSCs can be recognized by NK-cells rather than by autologous T-cells. We observed that iPS-fibro elicited a high level of NK-cell degranulation and cytotoxicity, while isogeneic parental skin fibroblasts used to obtain iPSCs barely triggered an NK-cell response. iPSC-derivatives with B2M knockout did not cause an additional increase in NK-cell activation, although they were devoid of HLA-I, the major inhibitory molecules for NK-cells. Transcriptome analysis revealed a significant imbalance of ligands for activating and inhibitory NK-cell receptors in iPS-fibro. Compared to parental fibroblasts, iPSC-derivatives had a reduced expression of HLA-I simultaneously with an increased gene expression of major activating ligands, such as MICA, NECTIN2, and PVR. The lack of inhibitory signals might be due to insufficient maturity of cells differentiated from iPSCs. In addition, we showed that pretreatment of iPS-fibro with proinflammatory cytokine IFNγ restored the ligand imbalance, thereby reducing the degranulation and cytotoxicity of NK-cells. In summary, we showed that iPSC-derived cells can be sensitive to the cytotoxic potential of autologous NK-cells regardless of HLA-I status. Thus, the balance of ligands for NK-cell receptors should be considered prior to iPSC-based cell therapies.

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Identification of RIFIN binding to KIR receptor from RIFIN expression library of Plasmodium flaicparum.

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