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.
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