Leukocyte immunoglobulin-like receptor subfamily B (LILRB3), also known as ILT5, LIR3, and CD85a, is an immunoglobulin superfamily member that is involved in immune regulation. Subfamily B members have cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that inhibit signaling events via phosphatase SHP-1. Subfamily A members are activating receptors that lack ITIMs and signal through association with FcR gamma (1, 2). Mature LILRB3 is a highly polymorphic 85-95 kDa glycoprotein that consists of a 420 amino acid (aa) extracellular domain (ECD) with four Ig-like domains, a 21 aa transmembrane segment, and a 167 aa cytoplasmic domain with three ITIMs (3). Alternative splicing generates an isoform with a 17 aa insertion in the juxtamembrane ECD. In mouse and rat, the LILRB3 gene encodes the PIR-B protein which has six Ig-like domains. Rodent PIR-B and human LILRB3 share 55% aa sequence identity within common regions of their ECDs. LILRB3 is expressed on the surface of peripheral monocytes, neutrophils, eosinophils, basophils, and mast cell progenitors (4-6). Triggering of LILRB3 inhibits the activation of macrophages, mast cells, neutrophils, basophils, and B cells (5, 7). On osteoclast precursors, LILRB3 ligation inhibits RANK L/TRANCE or M-CSF induced differentiation (8). LILRB3 can also bind to ligands exposed on necrotic tumor cells (9). Both PIR-B and LILRB3 are receptors for S. aureus, and activation of these receptors by bacteria influences the innate immune response triggered by TLRs (3). R&D Systems in-house testing indicates that LILRB3 binds to
Angiopoietin-like 7, consistent with the demonstrated functional interactions between other members of these protein families (10). In the mouse CNS, PIR-B functions as a receptor for the myelin proteins Nogo, MAG, and OMgp and mediates their inhibitory action on neurite outgrowth and axon regeneration (11). Upon binding to MAG, PIR-B associates with TrkB and NGF R/p75 in cerebellar granule neurons (12).