Paired immunoglobulin-like receptors and their MHC class I recognition

Abstract

The immunoglobulin-like receptors provide positive and negative regulation of immune cells upon recognition of various ligands, thus enabling those cells to respond properly to extrinsic stimuli. Murine paired immunoglobulin-like receptor (PIR)-A and PIR-B, a typical receptor pair of the immunoglobulin-like receptor family, are expressed on a wide range of cells in the immune system, such as B cells, mast cells, macrophages and dendritic cells, mostly in a pair-wise fashion. The PIR-A requires the homodimeric Fc receptor common gamma chain for its efficient cell-surface expression and for the delivery of an activation signal. In contrast, PIR-B inhibits receptor-mediated activation signals in vitro upon engagement with other activating-type receptors, such as the antigen receptor on B cells and the high-affinity Fc receptor for immunoglobulin E on mast cells. Recent identification of major histocompatibility complex (MHC) class I molecules as the physiological ligands for PIR has enabled us to attribute various immunological phenotypes observed in PIR-B-deficient mice to the consequences of the absence of a balanced interaction between PIR and MHC class I molecules expressed ubiquitously. Thus, PIR-A and PIR-B constitute a novel and physiologically important MHC class I recognition system.

Figure 1

Schematic structures of murine paired immunoglobulin-like receptor (PIR)-A and PIR-B and their close relatives or orthologues, chicken PIR (CHIR) and human leucocyte immunoglobulin-like receptors (LILR). Activating immunoglobulin-like receptors have a positively charged amino acid, Arg or His, in their transmembrane domains, which is involved in their interaction with negatively charged Asp residues of FcRγ homodimer. In contrast, inhibitory immunoglobulin-like receptors have several ITIM or ITIM-like sequences in their cytoplasmic portions important for SHP-1 recruitment upon tyrosine phosphorylation. GenBank accession numbers for PIR: U83172 AF040946 –040953 and AF041035 –041036 (as p91) and U96682 –96693. The multiple Pira and single Pirb genes locate near the centromeric region of mouse chromosome 7, syntenic to human leucocyte receptor complex (LRC) located in 19q.13·4. Fluorescence in situ hybridization analysis of rat PIR genes identified the locus 1q21.1–21·3, which is syntenic to the mouse chromosome 7 centromeric region, Repertoires of LILR are more complicated than those illustrated here (see http://www.gene.ucl.ac.uk/nomenclature/genefamily/lilr.html and extensively reviewed elsewhere,, It is also proposed that PIR-B could bind human HLA-B27

Figure 2

Schematic positive and negative signalling via PIR. Left, PIR-A on macrophages are expressed as a complex with an FcRγ homodimer, which have an ITAM. Interaction of PIR-A and PIR-B with MHC class I molecules will induce tyrosine phosphorylation of FcRγ and PIR-B. Right, schematic illustration of negative signalling via PIR-B on B cells upon constitutive interaction with MHC class I molecules on themselves (cis) or neighbouring cells (trans). Lyn and SHP-1 were constitutively associated with the tyrosine-phosphorylated cytoplasmic portion of PIR-B in B cells, mast cells and macrophages possibly upon continuous interaction with MHC class I molecules, suggesting that it is not necessary to co-crosslink between activating receptors, such as BCR and FcεRI, and PIR-B for the inhibitory effect in vivo. In fact, in Pirb^–/– B cells, BCR is hyperresponsive to anti-BCR stimulation