In addition to the KIRs and KLRs, which have a role in sensing the level of MHC class I proteins present on other cells, NK cells also express receptors that more directly sense the presence of infection or other perturbations in a cell. Activating receptors for the recognition of infected cells, tumor cells, and cells injured by physical or chemical damage include the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46, which are immunoglobulin-like receptors, and the C-type lectin-like family members Ly49H and NKG2D (Fig. 3.42). Among NCRs, only NKp46 is conserved in humans and in mice, and it is the most selective marker of NK cells across mammalian species. The ligands recognized by the NCRs are still being defined, but some evidence suggests that they recognize viral proteins, including the hemagglutinin (HA) glycoprotein of the influenza virus. Ly49H is an activating receptor that recognizes the viral protein m157, an MHC class I-like structure encoded by the murine cytomegalovirus. The ligand for NKp30 is a protein named B7-H6, a member of the family of co-stimulatory proteins mentioned in Section 1-15, and is further described in Chapters 7 and 9.
NKG2D has a specialized role in activating NK cells. NKG2 family members form heterodimers with CD94 and bind the MHC class I molecule HLA-E. In contrast, two NKG2D molecules form a homodimer that binds to several MHC class I-like molecules that are induced by various types of cellular stress. These include the MIC molecules MIC-A and MIC-B, and the RAET1 family of proteins, which are similar to the α1 and α2 domains of MHC class I molecules (Fig. 3.43). The RAET1 family has 10 members, 3 of which were initially characterized as ligands for the cytomegalovirus UL16 protein and are also called UL16-binding proteins, or ULBPs. Mice do not have equivalents of the MIC molecules; the ligands for mouse NKG2D have a very similar structure to that of the RAET1 proteins, and are probably orthologs of them. In fact, these ligands were first identified in mice as the RAE1 (retinoic acid early inducible 1) protein family, and also include related proteins H60 and MULT1 (see Fig. 6.26). We will return to these MHC-like molecules when we discuss the structure of the MHC molecule in Section 6-18.
The ligands for NKG2D are expressed in response to cellular or metabolic stress, and so are upregulated on cells infected with intracellular bacteria and most viruses, as well as on incipient tumor cells that have become malignantly transformed. Thus, recognition by NKG2D acts as a generalized ‘danger’ signal to the immune system. In addition to expression by a subset of NK cells, NKG2D is expressed by various T cells, including all human CD8 T cells, γ:δ T cells, activated murine CD8 T cells, and invariant NKT cells (described in Chapter 8). In these cells, recognition of NKG2D ligands provides a potent co-stimulatory signal that enhances their effector functions.