Targeting Inhibitory Immune Receptors in Inflammatory Disease, Guided by Molecular Understanding of Their Function

Immune inhibitory receptors are negative regulators of immune cells and, as such, dampen immune responses. Blocking inhibitory receptors in cancer results in not only powerful antitumor responses but also a diverse array of immune-related adverse events, reminiscent of inflammatory disease. The effects of blocking inhibitory receptors emphasize their importance in maintaining immune balance. Recent efforts therefore aim to therapeutically activate inhibitory immune receptors for the treatment of inflammatory conditions. To design effective ways to ligate inhibitory receptors and selectively induce inhibitory signaling in vivo, we must thoroughly grasp their mode of action. In this article, we review current understanding of the molecular mechanisms by which inhibitory immune receptors dampen inflammation. We particularly focus on ligand recognition and intracellular signaling and examine the state of the art of inhibitory receptor targeting in the clinic. Finally, we lay out the unknowns that must be addressed for the best therapeutic strategy to reap the benefits and mitigate potential risks of targeting inhibitory immune receptors in inflammatory diseases.