The function of natural killer (NK) cells is controlled by the balance between signals that are received from inhibitory and activating receptors. Ly49 genes in rodents encode both types of receptor; the main difference is that inhibitory receptors have cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs), whereas immunoreceptor tyrosine-based activation motifs (ITAMs) are found in the adaptor molecules — such as DAP12 — that associate with activating receptors. Although the extracellular domains of activating and inhibitory receptors are highly homologous, it is generally believed that they bind different ligands. Whereas inhibitory receptors bind MHC class I ligands, this does not seem to be the case for activating receptors, the ligands of which are largely uncharacterized. Now, two studies have shown that Ly49H, an activating receptor, can bind m157, an MHC-like molecule that is encoded by murine cytomegalovirus (MCMV).

Recent studies have shown that the expression of Ly49H is protective against infection with MCMV in resistant mice, but the mechanism of protection was unclear. To investigate this, Arase et al. developed reporter cells that were transfected with a nuclear factor of activated T cells (NFAT)–GFP reporter construct and the Ly49H protein, as well as the DAP12 adaptor molecule, which is essential for the activating function of Ly49H. When these cells were co-cultured with MCMV-infected cells, they turned green, which indicates the presence of a ligand for Ly49H on the infected cells. The Ly49H+ reporter cells could recognize MCMV-infected cells from β2-microglobulin-deficient and transporter for antigen processing (TAP)-deficient mice, which indicates that the ligand is unlikely to be a viral peptide presented by an MHC class I molecule. The viral ligand was identified as m157 using a panel of deletion mutants in this system.

Smith et al. used a similar approach to identify m157. They analysed the genome of MCMV, looking for open reading frames (ORFs) that have potential MHC folds, and they identified 12 such ORFs. Complementary DNAs were generated and transfected into cells, and the cells were assessed for their ability to interact with Ly49H+ NK cells. Only transfectants that expressed m157 were able to do so. It will be interesting to investigate the roles of the other 11 viral MHC-like molecules that were discovered.

However, it doesn't make much sense that MCMV expresses a viral protein that interacts with an activating NK-cell receptor to stimulate innate immune reactions. How does the virus benefit from retaining expression of m157? Smith et al. suggest that m157 might interfere with the host response by affecting the assembly and maturation of MHC class I molecules. Although this has not been discounted yet, an alternative possibility, suggested by both groups, is that Ly49H might also be able to interact with an inhibitory receptor, and that it is this interaction that is important for conferring host susceptibility in particular strains of mice. This was indeed found to be the case. Arase et al. suggest that 129/J mice are susceptible to MCMV infection because m157 is able to interact with Ly49I, an inhibitory receptor, which could provide a selective advantage to the virus by dampening immune responses. Arase et al. also speculate that activating NK-cell receptors could have evolved under pathogen-driven selective pressure.