Definition

NKG2D is an activating receptor (transmembrane protein) belonging to the C-type lectin-like receptor NKG2 family. NKG2D is encoded by the KLRK1 (killer cell lectin-like receptor K1) gene, which is located in the NK gene complex (NKC), which is located on chromosome 6 in mice and chromosome 12 in humans. In mice, it is expressed by NK cells, NK1.1+ T cells, γδ T cells, activated CD8+ αβ T cells, and activated macrophages. In humans, it is expressed as NK cells, γδT cells, and CD8+ αβT cells. NKG2D can recognize induced autoproteins from the MIC and RAET1/ULBP families, which are present on the surface of stressed, malignant transformed, and infected cells.

The NKG2D molecule, encoded by the Klrk1 gene, is an activated cell surface receptor that is mainly expressed on cytotoxic immune cells. Nkg2D is abundant in all NK cells, NKT cells and γδT cell subsets, and is also expressed on human naïve CD8+ T cells, but mouse CD8+ T cells are upregulated only after activation. In general, CD4+ T cells do not express NKG2D even after activation, but in humans, expression can be induced under certain pathological conditions, such as Crohn's disease, juvenile lupus, and cytomegalovirus infection.

Fig. 1 The Gene Structure of Human NKG2D.

Function

The NKG2D is the primary recognition receptor for detecting and eliminating transformed cells and infected cells because its ligand is induced during cellular stress, whether infectious or genomic stress, such as cancer in NK cells, NKG2D acts as an activating receptor, which itself is capable of triggering cytotoxicity. The effect of NKG2D on CD8+ T cells is to send co-stimulatory signals to activate them.

Role in Viral Infection

Viruses act as intracellular pathogens that can induce the expression of NKG2D stress ligands. NKG2D is considered important in viral control because viruses have adapted to mechanisms that evade the NKG2D response. [26] For example, cytomegalovirus (CMV) encodes the protein UL16, which binds to the NKG2D ligands ULBP1 and 2 (hence the name "UL16-binding protein") and MICB, thereby preventing their surface expression.

Role in Tumor Control

When cancer cells are "stressed" the NKG2D ligand is upregulated, leaving the cells vulnerable to NK cell-mediated lysis. However, some tumor cells have acquired the ability to evade this immune surveillance. They reduce and eliminate large amounts of NKG2DL present on the surface of tumor cells by secreting metalloproteinases that cleavage these ligands, so they escape the control of NK cells and their cytotoxic activity. TGF-β evades immune surveillance by inhibiting T and NK cell function. Therefore, tumor cells that are able to evade the NKG2D response are more likely to proliferate.

Role in the Removal of Senescent Cells

As part of the DNA damage response to induce cellular senescence, cells upregulate the expression of NKG2D ligands, enabling NK-mediated killing of senescent cells through the granule exocytopathy. Specifically, MICA and ULBP2 proteins on senescent cells are recognized by NKG2D receptors on natural killer cells, which are required for efficient recognition and elimination of senescent cells. Interventions that increase senescent cell surface ligands of the natural killer cell receptor NKG2D have been proposed as an anti-aging therapy to remove senescent cells.

NKG2D Signaling Pathway

The NKG2D-mediated activation signal can exceed the inhibitory signal of the NK inhibitory receptor, so NKG2D is the main activation receptor of NK cells. The NKG2D does not have any signaling elements in the intracellular domain, and NKG2D forms homodimers and associates its adaptor proteins in the transmembrane domain with the hexamer complex structure and initiates the signaling cascade.

In humans and mice, stable NKG2D surface expression requires the formation of a complex between the DNAX-activated protein (DAP10) of NKG2D and 10 kDa. In mice, NKG2D can also instantaneously bind ITAM (immunoreceptor tyrosine-based activation motif)—including DAP12, depending on the activation state of the cell. Upon binding, the Tyr-X-X-Meth (YXXM) motif within the DAP10 cytoplasmic domain recruits PI3K and Grb2 to activate the cytotoxic pathway of NK cells.

Fig. 2 The Interaction Between NKG2D and Its Ligands.

Clinical Application

NKG2D is an activating receptor and plays a very important role in NK cell activation. Nkg2D is mainly expressed in NK cells, most NKT cells, some T cell subsets, and is present on the surface of all human CD8+ T cells. NKG2D does not bind to CD94 and its ligands are MICA, MICB and ULBP1 in humans and Rae-1, H60 and MULT1 in mice. These ligands are not expressed or are poorly expressed in normal tissue cells, and can be induced to be expressed under stress conditions such as cell mutation and viral infection, and directly activated after binding to NKG2D or activated effector cells as co-stimulatory molecules to play an immune surveillance role.

Fig. 3 Functional Consequences of the Interaction of NKG2D with Different Ligand/Allelic Variants.

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