The SIRP family of receptors and immune regulation

Key Points The signal-regulatory proteins (SIRPs) can be classed as paired receptors, the most well known of which include the killer-cell immunoglobulin-like receptors, which are expressed by natural killer cells. The SIRP family contains activating, inhibitory and non-signalling members, which have closely related extracellular regions but distinct cytoplasmic tails. They are expressed mainly by myeloid cells and are therefore thought to have a role in immune regulation. Two types of ligand for the inhibitory member, SIRPα, have been identified: the widely expressed cell-surface protein CD47 and surfactant protein A. A third SIRP-family member, SIRPγ, transmits neither activating nor inhibitory signals even though it binds CD47. Like other paired receptors, the SIRPs show evidence of rapid evolution with considerable species differences and polymorphisms. Factors such as ligand availability, binding affinity, protein mobility and expression levels are likely to affect their function in vivo . Signal-regulatory proteins (SIRPs) are members of the paired-receptor family, which regulate and fine-tune immune responses. Their role in vivo is influenced by the different affinities of the SIRPs for their ligands and by their expression levels. The immune system must be highly regulated to obtain optimal immune responses for the elimination of pathogens without causing undue side effects. This tight regulation involves complex interactions between membrane proteins on leukocytes. Members of the signal-regulatory protein (SIRP) family, which are expressed mainly by myeloid cells, provide one example of these regulatory membrane proteins. There are three SIRP-family genes that encode proteins that have similar extracellular regions but different signalling potentials, and are therefore known as 'paired receptors'. In this Review, we describe recent studies defining the ligands of the SIRP-family members, with particular emphasis on relating the molecular interactions of these proteins to their role in immune-cell regulation.