Ly49 genes encode a large group of receptors that are located on the surface of mouse cells but that are not found in humans (Yokoyama and Plougastel, 2003). However, the Ly49 receptors are functionally similar to human KIRs despite their lack of sequence similarity. This receptor family is constituted of inhibiting receptors (Ly49 A, C, G, I) and activating receptors (Ly49D), which are restricted to recognition of murine MHC class I (i.e., H-2 molecules as they are termed in the mouse). One exception is Ly49H, which binds the murine CMV-derived m157 protein that is somewhat related to H-2 (Arase et al, 2002). As in the KIRs, the inhibiting signal overrides any activating signal that is generated by an Ly49 receptor.
Ly49 genes are type II transmembrane homodimeric receptors with a single lectin-like extracellular domain that recognizes its MHC ligand H-2. Inhibitory Ly49 receptors possess ITIM motifs in their cytoplas-mic regions, which function mechanistically like human ITIM motifs in inhibiting NK activation and granule movement. These receptors also recruit SHP-1 phosphatase to prevent phosphorylation of the essential kinases of NK activation. Ly49-activating receptors, as with human KIRs, lack an ITIM motif but instead associate with the ITAM-bearing DAP12 protein (Smith et al., 1998). This association is also similarly dependent on the interaction of the positively charged arginine residue of the transmembrane domain of the Ly49 receptor and the negatively charged aspartic acid residue of DAP12. Interestingly, the specific Ly49 repertoire and the amount of each Ly49 receptor directly depend on the H-2 expression of the host (Yokoyama and Plougastel, 2003). IL-12 and IL-18 treatment enables NK cells to mediate cytotoxicity and produce IFN-y despite expression of inhibitory receptors (Ortaldo and Young, 2003). These NK cells need two activating signals (activating Ly49 receptor and IL-12/IL-18) to overcome inhibition. These observations support the notion that temporary autore-activity could occur during acute inflammation from IL12/IL18 production by dendritic cells (DCs) that can induce IFN-y expression in NK cells, ultimately leading to expansion of the immune response. Another possible explanation for this phenomenon is that the main activating ligand for the Ly49 receptors is not H-2 but some other nonself protein. This assumption has been supported by multiple studies revealing that the murine CMV viral glycoprotein m157 is the specific ligand for Ly49H (Arase et al, 2002; Yokoyama and Plougastel, 2003). Recognition of this protein by NK cells provides in vivo protection against MCMV. As a balancing act, murine cytomegalovirus (MCMV) susceptibility is controlled by an inhibitory receptor Ly49I, which also recognizes the m157 glycoprotein. Thus, like human KIRs, there is a delicate interplay of activating and inhibitory receptors among the Ly49 family, dictated either by MHC class I or viral proteins to mediate NK function in mice.
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