The malaria parasite Plasmodium falciparum has evolved two distinct clades of RIFIN proteins that suppress NK cell function by targeting different conformational states of the inhibitory immune receptor LILRB1: one clade binds elongated LILRB1 to trigger trans-signaling, while a second clade stabilizes a buckled LILRB1 conformation that enhances cis-signaling through MHC class I on the same cell surface, representing the first experimental demonstration of functional cis-signaling through an inhibitory immune receptor and revealing how pathogens exploit conformational dynamics to evade immune surveillance.

The malaria parasite, Plasmodium falciparum, replicates within human erythrocytes, where it is susceptible to clearance by immune cells. It uses erythrocyte surface proteins, the RIFINs, to signal through immune receptors and to suppress immune cell function. Previous studies identified two groups of RIFINs which bind different sites on inhibitory immune receptor LILRB1. While some RIFINs bind an elongated LILRB1 conformation, triggering inhibitory immune signalling in ‘trans’, we show that other RIFINs stabilise a c-shaped LILRB1 conformation. This buckled LILRB1 binds MHC class I found on the same immune cell, which triggers inhibitory ‘cis’ signalling. Therefore, LILRB1 exists in dynamic equilibrium, with an elongated conformation able to bind to ligands in ‘trans’ on a target cell, while a buckled conformation signals through MHC class I in ‘cis’, setting the signalling threshold. Different clades of RIFINs exist to mediate inhibitory signalling through each of these LILRB1 conformations to prevent parasite destruction.