Immunity & infection
Cytomegaloviruses (CMVs) have evolved multiple mechanisms to subvert host immunity and establish successful long-term infections. To accomplish it, they encode a large repertoire of immune modulator genes, some of which derive from their host genomes after being captured at different points during host-virus co-evolution. CD48is a GPI-anchored protein that contains an ectodomain composed by 2 immunoglobulin (Ig) domains. Via its N-terminal Ig domain, CD48 recognizes the cell surface receptor 2B4. Engagement of 2B4 by CD48 results in the regulation of cytotoxic T lymphocyte and NK cell functions.We have recently reported the presence of a number of CD48 homologs (vCD48) encoded by different CMVs. Here, we have characterized the three vCD48 of owl monkey CMV, showing that they are highly glycosylated transmembrane proteins which display very distinctive structural and biochemical properties. Among them, only A43, the viral CD48 that exhibits the highest amino acid identity with host CD48 is able to bind 2B4, with the two other vCD48s having diverged to perform 2B4-independent functions. Interestingly, A43 is a soluble protein, released from the cell after being proteolitically processed through its stalk region. Kinetic studies revealed that A43:2B4 interactions are of exceptional affinity and highly stable. We demonstrate that purified soluble A43 efficiently blocks CD48:2B4 interactions. Furthermore, this viral protein is capable to impair immune-cell conjugate formation, interfering with the establishment of the mature NK cell synapse, and severely abrogating 2B4 mediated-NK cell cytotoxicity and interferon production. Thus, A43 acts as a functional virally-encoded CD48 decoy receptor.