Human cytomegalovirus, MHC class I and inhibitory signalling receptors: more questions than answers

The human cytomegalovirus UL18 protein, an MHC class I homologue, has been shown to bind to leucocyte immunoglobulin-like receptor (LIR)-1, a member o f a family of nine closely related immunoglobulin superfamily receptors exp ressed on leucocytes. The LIRs are related to the natural killer (NK)-cell immunoglobulin-like receptors and to several other immunoreceptors. Three g roups of LIR molecules have been defined: those containing cytoplasmic doma in inhibitory signalling motifs, those with short cytoplasmic domains and a charged residue within the transmembrane domain, and a secreted molecule. LIR-1 and LIR-2 bind to a broad spectrum of cellular MHC class I antigens, including HLA-A, -B and -C alleles. LIR-2 is expressed by all monocytes and dendritic cells, whereas LIR-1 is additionally expressed by B cells and su bsets of T and NK cells. Upon tyrosine phosphorylation, LIR-1 and LIR-2 ass ociate with the tyrosine phosphatase, SHP-1, and have been shown to inhibit Fc gamma RI signalling when co-crosslinked in monocytes. Evidence for and against a role of UL18 as an inhibitor of NK-cell function is discussed, as are possible functional outcomes of UL18-LIR-1 interactions in monocytic c ells.