Functional categories of immune inhibitory receptors.

The human genome encodes more than 300 potential immune inhibitory receptors. The reason for this large number of receptors remains unclear. We suggest that inhibitory receptors operate as two distinct functional categories: receptors that control the signalling threshold for immune cell activation and receptors involved in the negative feedback of immune cell activation. These two categories have characteristic receptor expression patterns: ‘threshold’ receptors are expressed at steady state and their expression remains high or is downregulated upon activation, whereas ‘negative feedback’ receptors are induced upon immune cell activation. We use mathematical models to illustrate their possible modes of operation in different scenarios for different purposes. We discuss how this categorization may impact the choice of therapeutic targets for immunotherapy of malignant, infectious and autoimmune diseases. Why does the human genome encode more than 300 potential immune inhibitory receptors? Here, the authors propose a categorization of inhibitory receptors — as threshold receptors and negative feedback receptors — that reflects their distinct functions in immune regulation, illustrated using mathematical modelling. This categorization may be useful for the therapeutic targeting of inhibitory receptors.