engleski

Mouse cytomegalovirus restores 'self' to prevent 'missing self'

Balance of signals coming from activating and inhibitory receptors expressed on the surface of NK cells regulates their response during acute mouse cytomegalovirus (MCMV) infection. In order to sidestep recognition by CD8+ T cells, CMVs encode proteins that downmodulate expression of MHC I on the surface of infected cells. Although this process should make infected cells prone to ‘missing-self’-mediated killing, in most laboratory mouse strains MCMV efficiently avoids early NK cell control. MCMV encodes three proteins involved in the regulation of MHC I expression. Whereas m152 and m06 downregulate MHC I, m04 instead binds to these proteins in the ER, forming complexes that reach the cell surface. We hypothesized that this mechanism evolved to prevent NK cell activation and killing by restoring the ‘self’ signature and allowing the engagement of inhibitory Ly49 receptors by their natural ligands. We have shown that indeed, the ligation of an inhibitory Ly49A NK cell receptor leads to a protection of infected cells from specific lysis, impaired proliferation of NK cells and loss of control of viral titer in mice of H-2d and H-2k haplotype, all during the first 3 days of infection (Babić et al, J Exp Med, 2010). In addition, we have shown that m04 is essential for the recognition of infected cells by the activating Ly49 receptors (Ly49P, Ly49P1, Ly49D2 and Ly49L), which restrictively recognize MHC I, together with m04 and another, unidentified viral component. Our results show that the recognition of MHC I/m04 complex by Ly49L+ NK cells in BALB.K mice leads to a specific expansion of this NK cell subset and increased IFN-γ production resulting in the faster clearance of infectious virus from the organ of these mice when compared to BALB/c or BALB.B mice (days 6-10 pi ; Pyzik et al, J Exp Med, 2011). Our current efforts are aimed to define the mechanisms leading to activation of NK cells in the context of the above described results.

MCMV; NK cells; Ly49 receptors; missing self

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