engleski

Downregulation of CD155 (PVR) by mouse cytomegalovirus

NK cells are equipped with a collection of activating and inhibitory receptors and thus, the NK activation status depends on the summation of their activating and inhibitory signals. Human CD155 (polio virus receptor, PVR), which is expressed by numerous tumors and healthy cells, is recognized by three different receptors: two co-stimulating receptors (CD96 and DNAM1) and one inhibitory receptor (TIGIT). All three receptors seem to be expressed by all NK cells. To investigate the interactions between PVR and its various receptors, we have cloned the mouse TIGIT receptor and demonstrated that it is an inhibitory receptor, as it interacts with the mouse PVR and inhibits NK cytotoxicity. We next showed that mouse PVR is regulated by murine cytomegalovirus (MCMV) causing its partial downregulation from the surface of infected cells. We have evidence that at least two MCMV gene products are involved in the downregulation of PVR. One of these is the m154 gene product, while the second MCMV gene still needs to be defined. We have also identified the mechanism for the other, so far undefined inhibitor, since we showed that it causes PVR retention in the endoplasmic reticulum (ER). The functional significance of PVR downregulation was demonstrated in vivo, namely, MCMV mutant lacking m154 gene is attenuated 3 days post infection. Since TIGIT binds PVR with high affinity as compared to DNAM1 and CD96, we suggest that the partial downregulation of PVR facilitates the escape from DNAM1 and CD96, while still enabling inhibition by TIGIT.

cytomegalovirus; CD155; PVR; immunoevasion; immunity

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