Leukocyte immunoglobulin-like receptors (LILRs) are a family of 13 highly homologous activating, inhibitory and soluble molecules localised within the leukocyte receptor complex in chromosome 19q13.4 (Borges and Cosman 2000). LILRs are primarily co-expressed on the surface of leukocytes of the innate immune system including monocytes, macrophages and neutrophils but also display limited expression on T, B and NK cells (Colonna et al. 1999, Borges and Cosman 2000). They are increasingly recognised as critical regulators of leukocyte activation by providing negative or positive signals (Colonna et al. 1999, Nakajima et al. 1999). Structurally, LILRs have two or four C-2 type Immunoglobulin-like homologous extracellular domains and differing transmembrane and cytoplasmic domains (Colonna et al 1999, Nakajima et al. 1999, Borges and Cosman 2000). Activating LILRs (A1, A2, A4, A5, A6) have short cytoplasmic domains lacking signalling motifs; the charged Argenine residue in their transmembrane domain links with immunoreceptor tyrosinebased activation motifs (ITAMs) of the FcR common γ chain, to facilitate activation via recruitment and phosphorylation of protein tyrosine kinase (PTK) signalling cascades (Nakajima et al. 1999, Borges and Cosman 2000) (Figs. 1 and 2). Inhibitory LILRs (B1, B2, B3, B4 and B5) have long cytoplasmic tails containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that transmit negative regulatory signals through recruitment of phosphatases that deactivate PTKs (Borges and Cosman 2000) (Figs. 1 and 2). Coengagement of activating and inhibitory LILRs on the surface of
leukocytes is emerging as critical to regulation of the threshold and amplitude of leukocyte activation, probably through shared ligands (Fig. 3). LILRA3 has no transmembrane domain and is predicted to be a secreted protein (Borges and Cosman 2000) (Fig. 2). Functionally, LILRA3 that bears close sequence similarity to the extracellular domains of activating LILRA1 (92 percent homology) and LILRA2
Figure 1 Schematic representation of inhibitory, activating and soluble leukocyte immunoglobulin-like receptors (LILRs). Activating, inhibitory and soluble LILRs have highly homologous two to four immunoglobulin-like extracellular domains that likely bind the same or related ligands. Activating LILRs have a positively charged arginine (R) in their transmembrane domain that binds to the aspartate residue (D) of the immunoreceptor tyrosine-based activation motif (ITAM)-containing common γ-chain of the Fc receptors (FcRγ). This ITAM transduces activation signals through phosphorylation of a cascade of non-receptor protein tyrosine kinases (PTK). Inhibitory LILRs contain long cytoplasmic domains consisting of two to four immunoreceptor tyrosine-based inhibitory motifs (ITIMs). When these pair with activating receptors they recruit phosphatases that deactivate PTKs and abrogate cellular activation. Soluble LILRs such as LILRA3 have no intracellular or transmembrane domain thus are likely to be secreted and act as an agonist or antagonist of closely related LILRs. Figure modifi ed from Borges and Cosman 2000.