NCR2 - natural cytotoxicity triggering receptor 2 |Elisa - Clia - Antibody - Protein

Background

Natural Cytotoxicity Triggering Receptor 2 (NCR2), also known as NKp44, is an activating receptor on the surface of natural killer (NK) cells. NK cells are crucial components of the innate immune system, specializing in the recognition and destruction of abnormal cells, including tumor cells and virus-infected cells. Unlike other immune cells, such as T and B lymphocytes, which rely on antigen-specific receptors, NK cells use NCR2 and other activating receptors to identify stressed, infected, or transformed cells without prior sensitization. This unique ability enables NK cells to mount a rapid immune response.

NCR2 is part of the NCR family, which also includes NCR1 (NKp46) and NCR3 (NKp30). These receptors, along with others like NKG2D, enable NK cells to recognize target cells that exhibit ligands associated with cellular stress or infection. NCR2 is specifically expressed on activated NK cells and is involved in both direct cytotoxicity and the secretion of cytokines and chemokines, amplifying the immune response. NCR2 plays an essential role in immune surveillance, contributing to the early detection and elimination of tumors and infection.

Protein Structure

NCR2 is a type I transmembrane protein that belongs to the immunoglobulin (Ig) superfamily, with a structural composition tailored for ligand binding and signal transduction. Its key structural features include:

Extracellular Domain:

• The extracellular region of NCR2 contains an Ig-like domain responsible for ligand recognition and binding. Unlike NCR1 and NCR3, NCR2 has a single Ig-like V-type domain, which is sufficient to bind various ligands.
• The V-type Ig domain is stabilized by disulfide bonds, contributing to the receptor's structural integrity and ligand specificity. This domain is responsible for recognizing and interacting with ligands on target cells, including both pathogen-derived molecules and stress-induced proteins on tumor cells.
• The extracellular domain has several glycosylation sites, which aid in maintaining the protein’s stability and enhancing its interactions with ligands. Glycosylation also influences NCR2’s surface expression on NK cells, impacting its functionality.

Transmembrane Domain:

• The transmembrane region of NCR2 contains a charged lysine residue, a key feature that facilitates its interaction with signaling adaptor proteins. This positively charged residue enables NCR2 to associate with DAP12, an adaptor protein containing an immunoreceptor tyrosine-based activation motif (ITAM).
• The DAP12 adaptor is necessary for NCR2 signaling, as it transmits activation signals from the extracellular domain to intracellular signaling pathways, leading to NK cell activation.

Intracellular Domain:

• The intracellular portion of NCR2 is relatively short and does not possess signaling motifs. Instead, NCR2 relies on DAP12 for signaling. Upon ligand binding to the extracellular domain, DAP12's ITAM undergoes phosphorylation, which then initiates downstream signaling events, resulting in NK cell activation and cytokine production.

The structure of NCR2 enables it to interact with a diverse range of ligands, including viral proteins, tumor-associated antigens, and other stress-induced ligands, positioning it as an important component of NK cell-mediated immune responses.

Classification and Subtypes

NCR2, classified under the natural cytotoxicity receptor (NCR) family, is one of the main activating receptors expressed on NK cells, along with NCR1 and NCR3. Each of these receptors plays a distinct role in recognizing various types of abnormal cells. Unlike NCR1, which is constitutively expressed on resting NK cells, NCR2 expression is induced upon NK cell activation, and it is predominantly expressed in peripheral blood NK cells and activated NK cells.

No major subtypes of NCR2 have been identified. However, some genetic polymorphisms and alternative splicing variants may influence the receptor's expression level, ligand-binding affinity, and downstream signaling efficiency. These genetic differences could impact individual immune responses, particularly in cancer and viral infections.

Function and Biological Significance

NK Cell Activation and Cytotoxicity:

• NCR2 plays a critical role in the activation of NK cells and subsequent cytotoxic responses. When NCR2 binds to its ligands on the surface of target cells, it triggers NK cell degranulation and release of cytotoxic granules containing perforin and granzymes, leading to apoptosis in the target cells.
• Alongside cytotoxic responses, NCR2 engagement induces the release of cytokines, such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). These cytokines enhance the immune response, recruiting additional immune cells and promoting inflammation at the infection or tumor site.

Recognition of Pathogen-Derived and Stress-Induced Ligands:

• NCR2 can recognize and bind a range of pathogen-derived ligands, including viral envelope proteins and bacterial components. One notable example is the interaction between NCR2 and certain viral hemagglutinins, such as those of influenza virus, allowing NCR2 to target and eliminate virus-infected cells.
• In addition to pathogen-derived ligands, NCR2 recognizes ligands that are overexpressed in stressed or transformed cells, such as tumor cells. This capability makes NCR2 an essential player in immune surveillance, contributing to early detection and elimination of potentially malignant cells.

Immune Modulation and Cytokine Secretion:

• NCR2 not only induces cytotoxicity but also modulates immune responses by secreting cytokines that enhance the activity of other immune cells. This cytokine release helps initiate and sustain inflammatory responses against tumors and infections, amplifying the immune system’s capacity to control disease.
• Through interactions with other activating receptors, such as NKG2D, NCR2 enhances the functional capacity of NK cells, enabling them to recognize and respond to a wider range of abnormal cells, thereby improving the efficacy of the immune response.

Clinical Issues

Cancer Immunotherapy:

• Given its role in tumor surveillance, NCR2 is a significant target in cancer immunotherapy. Strategies aiming to enhance NCR2-mediated NK cell activation, such as CAR-NK cells engineered to express NCR2, are under investigation. By increasing NCR2 activity, these therapies seek to improve NK cell cytotoxicity against cancer cells, potentially enhancing the effectiveness of immunotherapies against solid tumors and hematologic malignancies.
• Some cancers may downregulate NCR2 ligands as a mechanism to evade NK cell detection, contributing to immune escape. Understanding how to counteract this evasion strategy could enhance the effectiveness of NK cell-based immunotherapies.

Infectious Diseases:

• NCR2’s role in recognizing viral and bacterial ligands is essential in the early immune response to infections. Certain viruses and bacteria, however, can evade NK cell-mediated killing by interfering with NCR2 or its associated signaling pathways. This evasion tactic has implications for designing antiviral and antibacterial therapies that enhance NCR2 activity to counteract pathogen resistance.
• Additionally, genetic variations in NCR2 or its adaptors may impact an individual's susceptibility to infections and the efficiency of their immune response, making NCR2 a potential target for personalized immunotherapies in infectious disease management.

Autoimmunity and Inflammatory Disorders:

• Dysregulation of NCR2 activity has been linked to autoimmune and inflammatory diseases. In some cases, inappropriate activation of NCR2 can lead to NK cell-mediated damage to healthy tissues, contributing to chronic inflammation. This has been observed in certain autoimmune conditions where NCR2-expressing NK cells mistakenly target self-cells.
• Therapeutic strategies that modulate NCR2 signaling could potentially mitigate NK cell-mediated autoimmune responses, offering new avenues for managing autoimmune diseases.

Genetic Polymorphisms and Disease Susceptibility:

• Variations in the NCR2 gene have been associated with altered NK cell function and susceptibility to various diseases, including cancer, autoimmune disorders, and infections. Polymorphisms in NCR2 may affect the receptor's expression level, ligand affinity, and signaling efficiency, impacting the overall immune response. Research into these polymorphisms is ongoing, with potential implications for developing personalized therapies based on NCR2 genetics.

Summary

NCR2, also known as NKp44, is an activating receptor on NK cells that plays a critical role in immune surveillance and the body’s defense against tumors and pathogens. Structurally, NCR2 is a type I transmembrane protein with an Ig-like extracellular domain, a transmembrane region that binds the DAP12 adaptor, and a short intracellular tail. This structure enables NCR2 to recognize a diverse range of ligands on the surface of abnormal cells, initiating NK cell cytotoxicity and cytokine release.

Functionally, NCR2 mediates NK cell activation, enhancing immune responses through direct cytotoxicity and cytokine production. It binds to viral and bacterial ligands as well as stress-induced ligands on transformed cells, contributing to early detection and elimination of infected or malignant cells. The receptor's activation also amplifies immune responses, recruiting additional immune cells and enhancing inflammation in response to tumors and infections.

Clinically, NCR2 has significant therapeutic potential in cancer immunotherapy, infectious diseases, and autoimmune disorders. Enhancing NCR2 signaling could improve NK cell-mediated cancer cell killing, while modulating its activity might prevent autoimmune damage. Genetic variations in NCR2 also influence individual immune responses, offering potential for personalized therapies based on NCR2 gene profiling. As research continues, NCR2 remains a promising target in immunotherapy and immune regulation for various diseases.