Previous work has extensively shown that inhibitory receptors regulate cell activation in B, NK, mast cells, and subsets of T cells when co-ligated with ITAM-containing stimulatory receptor complexes. Our data extend this concept to professional APCs, showing that ILT3 negatively regulates APC functional responses triggered via stimulatory receptors, such as CD11b, CD16, and even MHC class II. In addition to its inhibitory function, ILT3 is involved in antigen uptake. It is noteworthy that ILT3 is expressed on DCs. These are a unique type of leukocytes whose primary function is to efficiently capture antigens, process them, and present them to naive T cells (57
). Although the uptake and processing of antigen is a major function of DCs, only a few mechanisms and receptors specialized for antigen capture have been identified on DCs (58
). Our data indicate that ILT3 is a unique receptor expressed in DCs, able to target the ligand into processing and peptide-loading compartments. Thus, ILT3 displays a dual function of inhibitory receptor and antigen-capturing molecule. A similar dual function has been previously shown for the low affinity receptor for IgG, FcγRIIB (7
The ligand of ILT3 is still unknown. ILT3 is closely related to bovine Fcγ2R and, to a lesser extent, to human FcαR, suggesting that ILT3 may be an Fc receptor. However, we did not detect any significant binding of human monomeric and heat-aggregated IgM, IgG, IgA, and IgE to ILT3-transfected Jurkat T cells (data not shown). ILT3 also shows homology to KIRs, which suggests that it may be a receptor for MHC class I molecules. We have investigated this possibility by analyzing binding of soluble ILT3HuIgG1 fusion protein to MHC class I transfectants in the class I–deficient mutant 721.221. No significant binding could be detected by FACS® analysis under the same experimental conditions in which KIR-HuIgG fusion proteins bind to MHC class I molecules (data not shown). We are investigating the possibility that ILT3 is a receptor for cell surface molecules related to MHC class I molecules, such as nonclassical class I molecules (CD1 , MR1 , MIC ), for MHC class II molecules, or for serum factors such as complement components.
ILT3 is a member of the ILT subfamily of Ig-SF molecules, which is located on chromosome 19, most likely in close linkage with KIRs. Another member of this family, ILT2, is characterized by similar cytoplasmic tyrosine-based motifs such as ILT3, and is expressed in B cell lines, suggesting that this may be a putative inhibitory resceptor in B cells. We have also cloned additional cDNAs which encode novel molecules homologous to ILT2 and ILT3 (ILT4 and ILT5, GenBank accession numbers AF000574 and AF000575). Thus, the number of Ig-SF inhibitory receptors with different tissue distribution and specificity is likely to increase.