KLRK1

What is KLRK1?

Natural killer cell (NK) has anti-tumor activity. Many kinds of receptors can be expressed on the surface of NK cells, which can be divided into active receptors and inhibitory receptors according to their function. NKG2D is a kind of activated receptors.

NKG2D was discovered by Houchins et al when screening the dominant expressed genes in human NK cells. NKG2D is also known as KLRK1, CD314, KLR and killer cell lectin-like receptor K1. It is a type Ⅱ transmembrane protein and a key member of the C-type lectin receptor family. It is an important activated receptor on the surface of immunoreactive cells such as NK cells, CD8 + γ δ T cells and γ δ T cells.

NKG2D receptors can specifically bind to NKG2D ligands on the surface of tumor cells and be activated, so as to achieve the purpose of killing tumor and play an important role in controlling tumor growth.

The Structure of KLRK1

The NKG2 gene complex is located on mouse chromosome 6 and human chromosome 12 respectively. The human NKG2D gene is located at 12p12.3-13.1 with a length of 270kb. The human NKG2D gene consists of 10 exons and 9 introns.

Exon 2-4 encodes intracellular and transmembrane domains, and exon 5-8 encodes extracellular domains that bind to ligands. The protein encoded by NKG2D is 42 kDa type Ⅱ membrane protein.

NKG2D is expressed as a homologous dimer whose extracellular domain is used for ligand binding.

Transmembrane region: the transmembrane region of NKG2D contains positively charged amino acids, which bind to adaptor proteins to complete NKG2D signal transduction.

Cytoplasmic domain: NKG2D has a short intracellular domain with charged amino acids interacting with DAP10 and / or DAP12, which are associated with signal transduction. The main junction protein of human NKG2D is that NKG2D of DAP10, mice can bind not only to DAP10 but also to DAP12.

The Expression of KLRK1

NKG2D was expressed in all NK cells, and was expressed in CD8 α β T cells, γ δ T cells, NKT, innate lymphoid cells (ILC) and CD4+T cells under some pathological conditions.

KLRK1 Ligands

NKG2D can bind to many different ligands, which belong to major histocompatibility complex class I (MHC-I) related proteins.

The first NKG2D ligand of mice belongs to the RAE-1 protein family. The other two NKG2D ligands in mice are MULT-1 and minor histocompatibility antigen H60.

In humans, NKG2D ligands include MICA/B and ULBPs. Human NKG2D ligand RAET-1 protein is homologous to mouse RAE-1 protein. Another family of human NKG2D ligands are MICA and MICB.

These ligands are almost not expressed in healthy cells and tissues, but are highly expressed on the surface of target cells in the state of infection or tumor.

The interaction between NKG2D and its ligands makes immune cells proliferate, secrete cytokines such as IFN- γ, GM-CSF, MIP-1 α and IL-2, and even lead to the dissolution of target cells.

The Function of KLRK1

In NK cells, NKG2D acts as an activation receptor, activating NK's innate immune response and leading to cytotoxic activities.

NK cells were induced to express NKG2D, which could regulate the differentiation and survival of NK cells and play an important role in the anti-tumor immune response.

Activation of NKG2D can induce the secretion of cytokines and chemokines and promote the proliferation of effector cells.

It is also involved in bone marrow transplantation rejection mediated by NK cells.

In CD8+T cells, NKG2D, as the costimulatory receptor of T cell receptor (TCR), sends costimulatory signals to enhance the activation of T cells.

NKG2D partially regulates immune inflammation and enhances antiviral effect by activating NK cells during HBV infection.

Decreased NKG2D expression is associated with gastric cancer progression.

Together with its multiple ligands, NKG2D forms a powerful stress-induced monitoring system that provides resistance to infection, inflammation, and malignant transformation of cells, and plays a decisive role in anti-tumor immune surveillance.

Binding of NKG2D ligands to NKG2D can trigger strong anti-tumor effects, suggesting that the NKG2D-mediated pathway may be a powerful target for the treatment of cancer.

Latest Research Progress

NKG2D ligand is generally absent on the surface of normal cells, but overexpressed on the surface of malignant cells, which provides a good target for CAR-T therapy.

The analysis of cancer genome and HCC tumor samples showed that the expression of most NKG2DLs in tumors was higher than that in normal tissues. The researchers designed a new NKG2D-based CAR-T cell: NKG2D-BBz CAR-T cell. It includes the extracellular domain of human NKG2D, 4-1BB, and CD3ζ signaling domains (BBz).

Studies have shown that NKG2D-BBz CAR-T cells can effectively remove hepatoma cells with high expression of NKG2DL, thus providing a promising therapeutic intervention for patients with NKG2DL-positive liver cancer.

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