Abstract
Natural Killer (NK) cells contribute to the control of viral infection by directly killing target cells and mediating cytokine release. In C57BL/6 mice, the Ly49H activating NK cell receptor plays a key role in early resistance to mouse cytomegalovirus (MCMV) infection through specific recognition of the MCMV-encoded MHC class I-like molecule m157 expressed on infected cells. Here we show that transgenic expression of Ly49H failed to provide protection against MCMV infection in the naturally susceptible A/J mouse strain. Characterization of Ly49H+ NK cells from Ly49h-A transgenic animals showed that they were able to mount a robust cytotoxic response and proliferate to high numbers during the course of infection. However, compared to NK cells from C57BL/6 mice, we observed an intrinsic defect in their ability to produce IFNγ when challenged by either m157-expressing target cells, exogenous cytokines or chemical stimulants. This effect was limited to NK cells as T cells from C57BL/6 and Ly49h-A mice produced comparable cytokine levels. Using a panel of recombinant congenic strains derived from A/J and C57BL/6 progenitors, we mapped the genetic basis of defective IFNγ production to a single 6.6 Mb genetic interval overlapping the Ifng gene on chromosome 10. Inspection of the genetic interval failed to reveal molecular differences between A/J and several mouse strains showing normal IFNγ production. The chromosome 10 locus is independent of MAPK signalling or decreased mRNA stability and linked to MCMV susceptibility. This study highlights the existence of a previously uncovered NK cell-specific cis-regulatory mechanism of Ifnγ transcript expression potentially relevant to NK cell function in health and disease.
Highlights
Natural killer (NK) cells are pivotal for both the destruction of virally-infected cells and for the cytolysis of certain tumor cells [1]
We found that even after proper recognition of infected cells by Natural Killer (NK) cells, the adequate production of IFNc is crucial to restrain viral infection
We found that Gzmb and Prf expression was drastically increased in Ly49H+ and Ly49H2 NK cells derived from the A-Ly49h mice compared to cells derived from B6 mice and, to a lesser extent, those derived from FVB-Ly49h mice (Figure S3D)
Summary
Natural killer (NK) cells are pivotal for both the destruction of virally-infected cells and for the cytolysis of certain tumor cells [1]. These processes are dependent on the interaction of NK cell receptors with their cognate ligands on target cells. Activating NK cell receptors detect specific pathogen–associated structures. These receptors lack an intracellular signaling domain and associate noncovalently with the immunoreceptor tyrosine-based activation motif–containing adaptor DAP12, CD3j or FceRIc or the TyrIle-Asn-Met motif–containing adaptor DAP10 [4]. Engagement of activating receptors results in cytoskeletal rearrangement, proliferation and the secretion of lytic granules and cytokines
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