NKG2D Receptor and Its Ligands in Host Defense

Abstract

NKG2D is an activating receptor expressed on the surface of natural killer (NK) cells, CD8(+) T cells, and subsets of CD4(+) T cells, invariant NKT cells (iNKT), and γδ T cells. In humans, NKG2D transmits signals by its association with the DAP10 adapter subunit, and in mice alternatively spliced isoforms transmit signals either using DAP10 or DAP12 adapter subunits. Although NKG2D is encoded by a highly conserved gene (KLRK1) with limited polymorphism, the receptor recognizes an extensive repertoire of ligands, encoded by at least eight genes in humans (MICA, MICB, RAET1E, RAET1G, RAET1H, RAET1I, RAET1L, and RAET1N), some with extensive allelic polymorphism. Expression of the NKG2D ligands is tightly regulated at the level of transcription, translation, and posttranslation. In general, healthy adult tissues do not express NKG2D glycoproteins on the cell surface, but these ligands can be induced by hyperproliferation and transformation, as well as when cells are infected by pathogens. Thus, the NKG2D pathway serves as a mechanism for the immune system to detect and eliminate cells that have undergone "stress." Viruses and tumor cells have devised numerous strategies to evade detection by the NKG2D surveillance system, and diversification of the NKG2D ligand genes likely has been driven by selective pressures imposed by pathogens. NKG2D provides an attractive target for therapeutics in the treatment of infectious diseases, cancer, and autoimmune diseases.

Figure 1

Mouse NKG2D receptor complex. Mice express two alternatively spliced isoforms of NKG2D. NKG2D-L (long) is expressed as a disulfide-bonded homodimer that can associate with DAP10 homodimers on the surface of resting mouse NK cells and on activated (but not resting) CD8⁺ T cells. After activation, mouse NK cells express a NKG2D-S (short) isoform that can associate with either homodimers of DAP10 or DAP12. DAP10 contains a YINM motif capable of recruiting a p85 PI3-kinase, Vav-1, Grb2 signaling complex whereas DAP12 contains a canonical ITAM, which can recruit Syk and ZAP70.

Figure 2

Human NKG2D receptor complex. Humans express a single full-length isoform of NKG2D constitutively as a disulfide-bonded homodimer on the cell surface of essentially all NK cells and CD8⁺ T cells, associated in a hexameric complex with two homodimers of the DAP10 signaling protein. Some individuals express an alternatively spliced NKG2D transcript that lacks the entire extracellular domain, but retains the transmembrane and cytoplasmic domains of NKG2D (NKG2D-TR). NKG2D-TR homodimers and heterodimers of NKG2D-TR and full-length NKG2D apparently associate with DAP10 homodimers, but are retained within the cytoplasm and degraded, thereby diminishing cell surface expression of functional NKG2D complexes.

Figure 3

This is a schematic diagram showing all human and mouse NKG2D ligands identified to date.