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Natural Killer (NK) cell activity is regulated by signals from numerous activating and inhibitory receptors.

The KIRs bind to HLA-A, -B or -C. The C-type lectin-like inhibitory CD94-NKG2A and activating CD94-NKG2C heterodimers interact with HLA-E.

Inhibitory receptors contain ITIM motifs and recruit tyrosine phosphatases.

Activating receptors associate with an adaptor molecule, DAP12, which contains an ITAM and recruits protein kinases.

Among the activating receptor, NKG2D, shares little similarity with other NKG2 proteins and is not associated with CD94. It pairs with an adaptor molecule, DAP10, which can signal by recruitment of phosphatidylinositol 3-kinase. NKG2D is expressed on most NK cells, CD8 α-β T cells, and γ-δ T cells and thus is the most widely expressed "NK cell receptor" known. Among its ligands is the MHC class I related, stress-inducible surface glycoprotein MICA, which has a limited tissue distribution in gastrointestinal epithelium and diverse epithelial tumors and is induced by CMV infection. Engagement of NKG2D by MICA triggers NK cells and co-stimulates some γ-δ T cells and antigen-specific CD8 α-β T cells.

The structure of MICA is similar to the protein fold of MHC class I, with an α1-α2 platform domain and a membrane-proximal immunoglobulin-like α3 domain. Unlike conventional class I molecules, however, MICA is not associated with β2-microglobulin (β2-m) and peptides. A closely related molecule, MICB, may also function as a ligand for NKG2D. Both MICA and MICB are polymorphic.

Sequences directly related to MIC are conserved in the genomes of most mammals with the probable exception of rodents. In the mouse, which lacks the MHC interval that encodes MIC genes in other species, a heterologous family of proteins, the Rae-1 molecules, function as ligands for NKG2D. These molecules share similarities with the human CMV UL16-binding proteins (ULBPs), which also interact with NKG2D. All of these molecules consist of an MHC class I α1-α2 platform-like domain that is attached to the cell membrane by a GPI anchor.

NKG2D is a type II disulphide-linked dimer with lectin-like domains.

Ligands for NKG2D

The ligands for human NKG2D are the HLA class Ib molecules, MICA and MICB whose expression is induced by stress, such as heat shock. NKG2D functions as an activation receptor by associating with a signaling chain, termed DAP10, encoded by a gene only a few bp away from the gene encoding another NK cell signaling chain, DAP12.

Whereas DAP12 signals via tyrosine phosphorylation of its ITAM, in much the same way as does CD3ζ in T cells, DAP10 has no ITAMs. Instead it has a site for apparent association with phosphatidylinositol-3 kinase (PI-3 kinase), implying distinct signaling mechanisms.

The ligands for mouse NKG2D are the inducible transmembrane protein H-60 and the glycosylphosphatidyl-inositol linked RAel molecules. H-60 serves as a minor histocompatibility antigen expressed in stimulated BALB/c but not C57BL/6 lymphoblasts. The RAel family, comprised of α, β, γ, and possibly δ isoforms, is induced in embryonal carcinoma cells upon exposure to retinoic acid.

CTL and NK cell cytotoxicity

MHC-I molecules on virus-infected cells present viral antigenic peptides to the T cell receptor (TR) of MHC-I-restricted cytotoxic T lymphocytes (CTL), thereby triggering CTL cytotoxicity. NK cells may not be triggered, due to inhibition by MHC-I (and possibly, the absence of activation receptor).

However, viral infections frequently result in significant down-regulation of MHC-I expression. By induction of expression of ligands, such as MICA and MICB in human, or RAel and H-60 in mouse, the target would then become susceptible to NK cells via NKG2D triggering release of cytotoxic granules. This may provide an important failsafe system to avoid pathogen strategies that evade T cell immunity and vice versa.

However, viral products may mask recognition of Rael and prevent killing.

NK cells express and can use at least three distinct ITAM-containing signaling chains (CD3ζ, Fcε RIγ and DAP12), both Syk family tyrosine kinases (Syk itself and ZAP70) as well as a variety of cytokine activation pathways.

The sequence similarity between the RAel family members and H-60 is relatively low yet NKG2D binds them all, suggesting that NKG2D is a promiscuous receptor. The RAel and H-60 molecules vaguely resemble MHC-I molecules but lack the α 3 domain that is required for β2-microglobulin association. NKG2D is apparently induced on macrophages and CD8+ T cells. Macrophages can be triggered through NKG2D to produce nitric oxide and TNFα. The expression of NKG2D on activated T cells and thymocytes may be relevant to T cell activation during development as well as clonal expansion or effector function. RAel expression is induced within 48h by retinoic acid. It is worth noting that retinoic acid is employed for chemotherapy of acute promyelocytic leukemia. Conventional wisdom suggests that retinoic acid induces differentiation of APL cells to terminal myeloid cells that have limited proliferation potential, creating a population of cells that then die by apoptosis. The recognition that retinoic acid can induce ligands for NK cells and macrophages which results in killing of target cells provides support for another possibility, involving display of these ligands on APL cells.

[1] Yakoyama, W. M. Nature Immunology 1, 95-97 (2000).