Polymorphisms in LILRB-1 affects its ligand interactions

Abstract

Abstract Leukocyte immunoglobulin-like receptor B-1 (LILRB-1) is an inhibitory receptor of the immunoglobulin super family expressed on a subset of natural killer (NK) cells. LILRB-1 binds a wide range of classical and non-classical MHC class I molecules, and a glycoprotein product of the human cytomegalovirus (HCMV), UL18. UL18 is a structural homolog of MHC class I expressed on the surface of infected cells. The two most distal domains of LILRB-1, denoted as D1 and D2, are the main contributors at the interaction interface of LILRB-1 with its ligands. Four non-synonymous polymorphisms within D1 and D2 domains produce LILRB-1’s natural variants. Interestingly, these variants have shown different expression and binding trends on NK cells and were suggested to affect susceptibility to HCMV infection in a cohort of kidney transplant recipients. Differences in the interaction of different LILRB-1 variants with their ligands such as, classical (HLA-Cw15) and non-classical MHC class I ligands (HLA-G) as well as UL18 have are assessed using a flowcytometry based binding assay and confirmed with functional assays. Our experiments show a trend of tight binding range of most LILRB-1 variants with HLA-G. However, the strength of binding is more variant with other classical MHC class I ligands, showing a constant trend based on the protein introduced by each of the four non-synonymous polymorphisms in different genotypes. Such findings may highlight an evolutionary pressure to maintain a relatively constant interaction of LILRB-1 with HLA-G, which is expressed on fetal trophoblasts to maintain maternal tolerance.