Inhibitory and Coactivating Receptors Recognising the Same Ligand: Immune Homeostasis Exploited by Pathogens and Tumours

Abstract

Coactivating and inhibitory receptors that share at least one ligand interact with a wide variety of ligands, indicating their importance in a range of situations. Here, we discuss principles of mainly human paired receptor function and ligand recognition, and possible therapeutic implications of targeting these receptors in cancer, autoimmune diseases, and allergy. We summarise and emphasise the idea that these receptors, which have evolved in part in response to pathogen pressure, fine-tune the immune response, preserve homeostasis, and that pathogens and tumours use the dominance of the inhibitory receptors over the coactivating receptors to avoid immune elimination. Finally, we discuss the options of using paired receptors and their ligand for immune cell education and therapy.

Trends

Paired receptors were initially described as activating and inhibitory receptors homologous in their extracellular domains and located in close proximity on the genome.

Here we give a broader definition, as a pair of receptors that includes an inhibitory and a coactivating receptor; where each member has at least one common cellular ligand, and upon binding, exerts contrasting effects (inhibition or co-stimulation).

In these pairs, the inhibitory receptor binds the shared ligand with greater affinity than does the coactivating receptor.

This high-affinity binding of the inhibitory receptor results also in competitive binding. Some of the inhibitory receptors can also exert their function by physically interacting with the activating receptor and preventing its activity.

Inhibitory receptors and ligands for paired receptors are used by pathogens and tumours for immune evasion.