engleski

ACTIVATING AND INHIBITORY LY49 RECEPTORS HAVE DIFFERENTIAL REQUIREMENTS FOR RECOGNITION OF MCMV-INFECTED CELLS

To prevent recognition by CD8+ T cells, cytomegaloviruses (CMVs) downmodulate the expression of MHC class I molecules. Although this process should make infected cells prone to ‘missing-self’-mediated killing, in most laboratory mouse strains, murine CMV (MCMV) efficiently avoids early NK cell control. We have previously shown that MCMV prevents NK cell activation and killing by restoring the ‘self’ signature and allowing the engagement of inhibitory Ly49A receptor by their natural ligands. In addition, we have shown that m04 is essential for the recognition of infected cells by the activating Ly49 receptors (Ly49P, Ly49L and Ly49D2), which recognize MHC I, together with m04. However, m04 in itself is not sufficient for the activation of reporter cells expressing activating Ly49P receptor, suggesting requirements for additional factor(s). By using a panel of MCMV deletion mutants we were able to show that this additional factor is located in the genomic region containing ORFs m167-m170. Deep sequencing, cDNA and RACE analysis of this region revealed the existence of a single, 1.7 kb long transcript. This transcript is the most abundantly transcribed viral transcript which was recently shown to act as a sponge for cellular miRNA miR-27. In addition, we have identified a poorly translated protein corresponding mostly to predicted ORF m169 making it unique among other herpesviral transcripts. However, none of these two coding and non-coding functions are responsible for recognition by activating Ly49 receptors. Only the deletion of 5’ UTR of the transcript abolished activating Ly49 recognition. Altogether, our results suggest that activating and inhibitory Ly49 receptors have differential requirements for recognition of MCMV-infected cells, suggesting more stringent conditions that allow activation of NK cells.

MCMV; MHC class I; NK cell; Ly49A

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