The KLR family also has both activating and inhibitory members. In mice, inhibitory Ly49 receptors have an ITIM in their cytoplasmic tail that recruits SHP-1. The latter’s importance is shown by the failure of Ly49 to inhibit NK activation upon binding to MHC class I in mice carrying the motheaten mutation, which inactivates SHP-1 protein. In humans and mice, NK cells express a heterodimer of two different C-type lectin-like receptors, CD94 and NKG2. This heterodimer interacts with nonpolymorphic MHC class I-like molecules, including HLA-E in humans and Qa1 in mice. HLA-E and Qa1 are unusual in that instead of binding peptides derived from pathogens, they bind fragments of the signal peptide derived from other MHC class I molecules during processing in the endoplasmic reticulum. This enables CD94:NKG2 to detect the presence of several different MHC class I variants, whose expression may be targeted by viruses, and kill cells in which overall MHC molecule expression is diminished. In humans there are four closely related NKG2 family proteins, NKG2A, C, E, and F (encoded by KLRC1–4), and a more distantly related protein, NKG2D (encoded by KLRK1). Of these, for example, NKG2A contains an ITIM and is inhibitory, whereas NKG2C has a charged transmembrane residue, associates with DAP12, and is activating (see Fig. 3.41). NKG2D is also activating but quite distinct from the other NKG2 receptors, and we will discuss it separately below.
The overall response of NK cells to differences in MHC expression is further complicated by the extensive polymorphism of KIR genes, with different numbers of activating and inhibitory KIR genes being found in different people. This may explain why NK cells are a barrier to bone marrow transplantation, since the NK cells of the recipient may react more strongly to donor MHC molecules than to the self MHC with which they developed. A similar phenomenon may occur during pregnancy, because of differences between fetal and maternal MHC molecules (see Section 15-38). The advantage of such extensive KIR polymorphism is not yet clear, and some genetic epidemiologic studies even suggest an association between certain alleles of KIR genes and earlier onset (although not absolute frequency) of rheumatoid arthritis. The KIR gene cluster is not present in mice, but some species, including some primates, contain genes of both the KIR and KLR families. This might suggest that both gene clusters are relatively ancient and that for some reason, one or the other gene cluster was lost by mice and humans.
Signaling by the inhibitory NK receptors suppresses the killing activity and cytokine production of NK cells. This means that NK cells will not kill healthy, genetically identical cells with normal expression of MHC class I molecules, such as the other cells of the body. Virus-infected cells, however, can become susceptible to being killed by NK cells by a variety of mechanisms. First, some viruses inhibit all protein synthesis in their host cells, so that synthesis of MHC class I proteins would be blocked in infected cells, even while their production in uninfected cells is being stimulated by the actions of type I interferons. The reduced level of MHC class I expression in infected cells would make them correspondingly less able to inhibit NK cells through their MHC-specific receptors, and they would become more susceptible to being killed. Second, many viruses can selectively prevent the export of MHC class I molecules to the cell surface, or induce their degradation once there. This might allow the infected cell to evade recognition by cytotoxic T cells but would make it