Fig. 3.41 The structural families of NK receptors encode both activating and inhibitory receptors. The families of killer cell immunoglobulin-like receptors (KIRs) and killer cell lectin-like receptors (KLRs) have members that send activating signals to the NK cell (upper panel) and those that send inhibitory signals (lower panel). KIR family members are designated according to the number of immunoglobulin-like domains they possess and by the length of their cytoplasmic tails. Activating KIR receptors have short cytoplasmic tails and bear the designation ‘S.’ These associate with the signaling protein DAP12 via a charged amino acid residue in the transmembrane region. The cytoplasmic tails of DAP12 contain amino acid motifs called ITAMs, which are involved in signaling. NKG2 receptors belong to the KLR family, and, whether activating or inhibitory, form heterodimers with another C-type lectin-like family member, CD94. The inhibitory KIR receptors have longer cytoplasmic tails and are designated ‘L’; these do not associate constitutively with adaptor proteins but contain a signaling motif called an ITIM, which when phosphorylated is recognized by inhibitory phosphatases.
Fig. 3.42 Activating receptors of NK cells include the natural cytotoxicity receptors and NKG2D. The natural cytotoxicity receptors are immunoglobulinlike proteins. NKp30 and NKp44, for example, have an extracellular domain that resembles a single variable domain of an immunoglobulin molecule. NKp30 and NKp46 activate the NK cell through their association with homodimers of the CD3ζ chain, or the Fc receptor γ chain (not shown). These signaling proteins also associate with other types of receptors that are described in Chapter 7. NKp44 activates the NK cell through their association with homodimers of DAP12. NKp46 resembles the KIR-2D molecules in having two domains that resemble the constant domains of an immunoglobulin molecule. NKG2D is a member of the C-type lectin-like family and forms a homodimer, and it associates with DAP10. In mice, an alternatively spliced form of NKG2D also associates with DAP12 (not shown).
The ligands for NKG2D are MHC-like molecules, MIC-A, MIC-B, or RAET1 family members, whose expression is induced by cellular stress MIC-A or MIC-B RAET1 family (includes MULT1, ULBPs) susceptible to being killed by NK cells. Virally infected cells can still be killed by NK cells even if the cells do not downregulate MHC, provided that ligands for activating receptors are induced. However, some viruses target ligands for the activating receptors on NK cells, thwarting NK-cell recognition and killing of virus-infected cells 3-27 NK cells express activating receptors that recognize ligands induced on infected cells or tumor cells.