FDF03, a Novel Inhibitory Receptor of the Immunoglobulin Superfamily, Is Expressed by Human Dendritic and Myeloid Cells

Abstract

In this study, we describe human FDF03, a novel member of the Ig superfamily expressed as a monomeric 44-kDa transmembrane glycoprotein and containing a single extracellular V-set Ig-like domain. Two potential secreted isoforms were also identified. The gene encoding FDF03 mapped to chromosome 7q22. FDF03 was mostly detected in hemopoietic tissues and was expressed by monocytes, macrophages, and granulocytes, but not by lymphocytes (B, T, and NK cells), indicating an expression restricted to cells of the myelomonocytic lineage. FDF03 was also strongly expressed by monocyte-derived dendritic cells (DC) and preferentially by CD14+/CD1a− DC derived from CD34+ progenitors. Moreover, flow cytometric analysis showed FDF03 expression by CD11c+ blood and tonsil DC, but not by CD11c− DC precursors. The FDF03 cytoplasmic tail contained two immunoreceptor tyrosine-based inhibitory motif (ITIM)-like sequences. When overexpressed in pervanadate-treated U937 cells, FDF03 was tyrosine-phosphorylated and recruited Src homology-2 (SH2) domain-containing protein tyrosine phosphatase (SHP)-2 and to a lesser extent SHP-1. Like engagement of the ITIM-bearing receptor LAIR-1/p40, cross-linking of FDF03 inhibited calcium mobilization in response to CD32/FcγRII aggregation in transfected U937 cells, thus demonstrating that FDF03 can function as an inhibitory receptor. However, in contrast to LAIR-1/p40, cross-linking of FDF03 did not inhibit GM-CSF-induced monocyte differentiation into DC. Thus, FDF03 is a novel ITIM-bearing receptor selectively expressed by cells of myeloid origin, including DC, that may regulate functions other than that of the broadly distributed LAIR-1/p40 molecule.

CD85j (Leukocyte Ig-Like Receptor-1/Ig-Like Transcript 2) Inhibits Human Osteoclast-Associated Receptor-Mediated Activation of Human Dendritic Cells

“…Intracellular Ca 2ϩ mobilization was determined as described previously (19), with modifications. Briefly, mono-DCs were loaded with 10 M Fluo-3AM and 5 M Pluronic F-27 (Molecular Probes) for 30 min at 37°C.…”

“…This growing family of receptors was described first in lymphocytes (14 -16). However, in recent years, an increasing number of receptors that are members of the lectin family and of the Ig superfamily and are linked to ITAM/ITIM signaling have been described on myeloid cells and DCs, such as Fc␥R, C-type lectin receptors (DC immunoactivating receptor), Ig-like transcript (ILT)3, ILT4, and FDF03 (17)(18)(19)(20)(21)(22).…”

Evolutionarily Conserved Paired Immunoglobulin-like Receptor α (PILRα) Domain Mediates Its Interaction with Diverse Sialylated Ligands

“…Human paired immunoglobulin-like receptors (PILR) 2 ␣ and ␤ are related type I transmembrane receptors. PILR␣ and -␤ share high similarity in their extracellular domain but contain highly divergent intracellular signaling domains and resulting functions (4,5). PILR␣ is predominantly expressed in cells of the myelomonocytic lineage, including monocytes/macrophages, granulocytes, and dendritic cells (4,6).…”

“…PILR␣ is predominantly expressed in cells of the myelomonocytic lineage, including monocytes/macrophages, granulocytes, and dendritic cells (4,6). PILR␣ has two cytoplasmic immunoreceptor tyrosine-based inhibitory motifs that recruit SHP-1 and SHP-2 to trigger an inhibitory signaling cascade such as reduced intracellular calcium mobilization (4,5). PILR␤, however, associates with the immunoreceptor tyrosinebased activation motif-bearing DAP12 adaptor molecule to deliver activating signals (6).…”

“…PILR␣ and -␤ share high similarity in their extracellular domain but contain highly divergent intracellular signaling domains and resulting functions (4,5). PILR␣ is predominantly expressed in cells of the myelomonocytic lineage, including monocytes/macrophages, granulocytes, and dendritic cells (4,6). PILR␣ has two cytoplasmic immunoreceptor tyrosine-based inhibitory motifs that recruit SHP-1 and SHP-2 to trigger an inhibitory signaling cascade such as reduced intracellular calcium mobilization (4,5).…”