LILRB1 polymorphisms influence posttransplant HCMV susceptibility and ligand interactions

Area of Science:

• Immunology
• Virology
• Genetics

Background:

• Human cytomegalovirus (HCMV) utilizes UL18, an MHC class I homolog, to inhibit Natural Killer (NK) cells expressing leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1).
• LILRB1 plays a critical role in NK cell recognition and immune regulation, with polymorphisms potentially influencing susceptibility to viral infections and pregnancy outcomes.

Purpose of the Study:

• To investigate the association between LILRB1 polymorphisms and HCMV control in transplant patients.
• To characterize the functional impact of naturally occurring LILRB1 variants on interactions with viral and host ligands, including UL18, classical MHC class I (MHCI), and HLA-G.

Main Methods:

• Analysis of LILRB1 polymorphisms in regulatory and ligand-binding regions in transplant patients.
• Expression of LILRB1 variants in model NK cells to assess functional recognition of UL18, MHCI, and HLA-G.
• Binding assays utilizing LILRB1 binding domains to quantify interactions with ligands.

Main Results:

• LILRB1 polymorphisms in regulatory and ligand-binding domains were associated with HCMV control.
• Naturally occurring LILRB1 variants exhibited differential functional recognition of UL18 and classical MHCI, but not HLA-G.
• Four nonsynonymous substitutions in LILRB1's immunoglobulin domains influenced binding to UL18, MHCI, and HLA-G. One polymorphism affected N-linked glycosylation, altering ligand binding, notably enhancing UL18 binding.

Conclusions:

• Specific LILRB1 alleles conferring enhanced HCMV immune evasion are counteracted by mutations limiting LILRB1 expression on NK cells.
• These LILRB1 polymorphisms maintain appropriate interactions with HLA-G, supporting its role in fetal tolerance.