Immobile ligands enhance FcgR-TLR2/1 crosstalk by promoting interface overlap of receptor clusters

Innate immune cells detect pathogens through simultaneous stimulation of multiple receptors, but how cells use the receptor crosstalk to elicit context-appropriate responses is unclear. Here, we reveal that the inflammatory response of macrophages from FcyR-TLR2/1 crosstalk inversely depends on the ligand mobility within a model pathogen membrane. The mechanism is that FcyR and TLR2/1 form separate nanoclusters that interact at their interfaces during crosstalk. Less mobile ligands induce stronger interactions and more overlap between the receptor nanoclusters, leading to enhanced signaling. Different from the prevailing view that immune receptors colocalize to synergize their signaling, our results show that FcyR-TLR2/1 crosstalk occurs through interface interactions between non-colocalizing receptor nanoclusters, which are modulated by ligand mobility. This suggests a mechanism by which innate immune cells could use physical properties of ligands to fine-tune host responses.

Automated summary

The crosstalk between FcyR and TLR2/1 receptors occurs through interface interactions between non-colocalizing receptor nanoclusters and is modulated by ligand mobility.