Identification of mouse cytomegalovirus immunoevasins that modulate NK cell recognition via the NKR-P1B:Clr-b axis (INM8P.403)

Abstract

Abstract Natural killer (NK) cells are a subset of innate lymphoid cells (ILC) capable of recognizing pathological target cells through germline-encoded receptor-ligand interactions. Mouse cytomegalovirus (MCMV) is a beta-herpesvirus that has co-evolved with its murine host, and as such, a significant portion of its genome encodes immunoevasins that directly target NK cell receptor-ligand interactions. Here, we identify two putative immunoevasins that modulate host-pathogen interactions via the inhibitory NKR-P1B:Clr-b recognition system. First, we identify an m145 family member that actively prevents MCMV infection-mediated Clr-b downregulation. Ectopic expression of this m145 family member in mouse fibroblasts increases Clr-b expression at the cell surface. In contrast, infection with an m145-family deletion mutant shows more substantial Clr-b loss at the cell surface compared to wild-type MCMV infection. Importantly, enhanced Clr-b loss upon infection with the deletion mutant could be reversed by complementation experiments involving overexpression of the m145 family immunoevasin. Secondly, we have identified an immunoevasin that directly interacts with the NKR-P1B inhibitory receptor, suggestive of decoy ligand function. This interaction is MCMV strain-dependent and host NKR-P1B allele-specific, suggesting that polymorphisms have evolved at both the pathogen and host levels that affect NK cell recognition of infected target cells.