engleski

THE MOUSE CYTOMEGALOVIRUS PROTEIN PREVENTS NK CELL ACTIVATION VIA „MISSING SELF“ MECHANISM

Like many other viruses, MCMV compromises antigen presentation by downmodulating major histocompatibility complex (MHC-I) class I molecules. Yet, since surface MHC-I molecules also serve as ligands for inhibitory NK cell receptors, this utility sensitizes the infected cells to NK cells via „missing self“-recognition mechanism. Therefore, during the co-evolution with their animal host CMVs had to develop strategies to avoid both CD8+ T and NK cell mediated immune responses. MCMV encodes three proteins that regulate MHC class I molecules. While two of them, m152 and m06, through different mechanisms, prevent surface expression of MHC class I, the third molecule, m04, binds to MHC class I in endoplasmic reticulum (ER), forming complexes that can reach the cell surface. We have recently shown that the recognition of MCMV-infected cells expressing H-2Dk and m04 via activating Ly49P receptor is associated with NK cell-mediated resistance in the MA/My mice (Kielczewska et al., J Exp Med, 2009). However, it has been proposed (Kleijnen et al., EMBO J, 1997) that MCMV m04 might serve the virus to inhibit NK cells by providing ligands to inhibitory NK cell receptors. Here we show that the virus lacking m04 is attenuated in NK cell- and MHC class I-dependent manner in several mouse strains. Furthermore, by using the reporter cell assay, we provide evidence that the presence of m04 during WT MCMV infection can rescue the engagement of inhibitory Ly49 receptors, despite the presence of two other inhibitors of MHC class I molecules. Altogether, our results show the novel mechanism of cytomegalovirus evasion of NK cells and at the same time help us to understand the effector mechanism of a “missing-self “ mediated recognition by NK cells.

MCMV; MHC-I; NK cells; Ly49 receptors

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