Why So Many Coinhibitory Receptors?

Receptors that display negative signalling functions on lymphocytes and other cells of the reticuloendothelial system now number about 30. These negative receptors are transmembrane glycoproteins activated by phosphorylation of a tyrosine residue in immunoreceptor tyrosine‐based inhibitory motifs that bind various phosphatases to induce dominant negative signals. Since these receptors are armed by the action of activating receptors and inhibit signalling by activating receptors, we have termed them coinhibitory receptors and the negative outcome is coinhibition. Coinhibitory receptors and some inhibitory mediators include FcγRIIB, CTLA‐4, CD5, CD22, p58/70/140 KIR, gp49B1/gp91, PIRB1‐5, LAIR‐1, NKB1, Ly49 A/C/E/F/G, NKG2‐A/B APC‐R, CD66, CD72, PD‐1, SHPS‐1, SIRP‐α1, ILT1‐5, MIR7,10, hMIR(HM18), hMIR(HM9), LIR1‐3,5,8, Fas (CD95), TGFβ‐R, TNF‐R1, IFNγ‐R (α and β chains), mast cell function Ag, H2‐M, HLA‐DM, CD1, CD1‐d, CD46, c‐cbl, Pyk2/FADK2, P130 Ca rel prot, PGDF‐R, LIF, LIF‐R, CIS, SOCS13 and 5, and others are being defined regularly. This long list suggests that coinhibitors are needed not only for self–nonself discrimination, but also for control of ongoing responses to foreign antigens so that infectious agents are ideally dealt with by an appropriate level of immune responses to nonself and an appropriate amount of immunopathology and sickness behaviour.