Cytomegalovirus m154 Hinders CD48 Cell-Surface Expression and Promotes Viral Escape from Host Natural Killer Cell Control

Abstract

Receptors of the signalling lymphocyte-activation molecules (SLAM) family are involved in the functional regulation of a variety of immune cells upon engagement through homotypic or heterotypic interactions amongst them. Here we show that murine cytomegalovirus (MCMV) dampens the surface expression of several SLAM receptors during the course of the infection of macrophages. By screening a panel of MCMV deletion mutants, we identified m154 as an immunoevasin that effectively reduces the cell-surface expression of the SLAM family member CD48, a high-affinity ligand for natural killer (NK) and cytotoxic T cell receptor CD244. m154 is a mucin-like protein, expressed with early kinetics, which can be found at the cell surface of the infected cell. During infection, m154 leads to proteolytic degradation of CD48. This viral protein interferes with the NK cell cytotoxicity triggered by MCMV-infected macrophages. In addition, we demonstrate that an MCMV mutant virus lacking m154 expression results in an attenuated phenotype in vivo, which can be substantially restored after NK cell depletion in mice. This is the first description of a viral gene capable of downregulating CD48. Our novel findings define m154 as an important player in MCMV innate immune regulation.

Author Summary

Cytomegalovirus (CMV) has developed diverse tactics to elude the host immune response and guarantee its survival. The signalling lymphocyte-activation molecules (SLAM) family of receptors encompasses a number of adhesion molecules expressed on the surface of leukocytes that play critical roles in both innate and adaptive immunity. In this study, we report that murine CMV drastically reduces the expression of several SLAM family receptors at the cell surface of infected macrophages, most likely as part of its immunoevasion mechanisms. We have identified a murine CMV gene product (m154) that downregulates CD48, a SLAM family member that functions as a ligand of CD244, a molecule involved in the regulation of natural killer (NK) and cytotoxic T cell functions. We show that during infection, m154 targets CD48 for degradation. Moreover, this viral protein contributes to increased MCMV growth during acute infection in the mouse by protecting against NK cell mediated surveillance. These findings are important for better understanding CMV pathogenesis, and provide a novel example of host innate immune subversion by CMV.