Natural Killer (NK) Cells- Definition, Structure, Immunity, Functions

Natural killer (NK) cells are a type of white blood cells that belong to the innate immune system. They are called natural killers because they can kill infected or abnormal cells without prior activation or recognition. They are essential for fighting against viral infections, cancer and other diseases.

NK cells are part of the lymphocyte family, which also includes B cells and T cells. However, unlike B cells and T cells, which have specific receptors for recognizing antigens, NK cells have a variety of receptors that can sense stress signals, such as the absence of self molecules or the presence of foreign molecules on the surface of target cells.

NK cells can be activated by cytokines, such as interferon-alpha and interleukin-12, which are produced by other immune cells in response to infection or inflammation. Once activated, NK cells can perform two main functions: cytotoxicity and cytokine production.

Cytotoxicity is the ability of NK cells to kill target cells by releasing granules that contain perforin and granzymes. Perforin forms pores on the membrane of the target cell, allowing granzymes to enter and trigger apoptosis (programmed cell death). NK cells can also induce cell death by expressing death ligands, such as Fas ligand and TRAIL, that bind to death receptors on the target cell.

Cytokine production is the ability of NK cells to secrete various molecules that modulate the immune response. For example, NK cells can produce interferon-gamma, which enhances the activity of macrophages and cytotoxic T cells; tumor necrosis factor-alpha, which induces inflammation and cell death; and interleukins, which regulate the differentiation and proliferation of other immune cells.

NK cells are found in various tissues and organs of the body, such as the blood, spleen, lymph nodes, liver, lung and uterus. They can also migrate to sites of infection or injury. NK cells are heterogeneous in their phenotype and function, depending on their developmental stage, activation state and microenvironment.

NK cells play a crucial role in immunity by eliminating infected or abnormal cells that escape from other immune mechanisms. They also interact with other immune cells to coordinate and regulate the immune response. NK cells are involved in various diseases, such as viral infections, cancer, autoimmune disorders and pregnancy complications.

In this article, we will discuss the definition, structure, immunity and functions of NK cells in more detail. We will also explore some of the current research and applications of NK cells in immunology and medicine.

Natural killer (NK) cells are a type of lymphocyte that belongs to the innate immune system. They are able to recognize and kill cells that are infected by viruses, bacteria, or other pathogens, as well as cells that are stressed, damaged, or transformed into tumor cells.

Unlike other lymphocytes, such as T and B cells, NK cells do not need prior activation or specific antigen recognition to perform their cytotoxic function. They can respond quickly and spontaneously to a wide range of targets by sensing the presence or absence of certain molecules on the cell surface.

NK cells are derived from a common lymphoid progenitor in the bone marrow, along with other lymphocytes. They then differentiate and mature in various lymphoid tissues, such as the spleen, lymph nodes, tonsils, and thymus. They circulate in the blood and can migrate to different tissues where they encounter potential targets.

NK cells account for about 5-20% of all circulating lymphocytes in humans. They are large, granular cells with a convoluted nucleus and a cytoplasm filled with granules that contain cytotoxic molecules. They also express various receptors on their surface that allow them to interact with other cells and molecules of the immune system.

NK cells are classified as group I innate lymphoid cells (ILCs), which are a family of immune cells that regulate inflammation, tissue homeostasis, and immunity. NK cells have both cytolytic and cytokine-producing effector functions that contribute to the elimination of pathogens and tumors, as well as the modulation of other immune responses.

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Natural killer cells are a part of the group consisting of other lymphoid cells like B and T lymphocytes. Lymphocytes are a type of white blood cell that help the immune system fight infections and cancer. They are found in the blood and lymph, which is a fluid that circulates through the lymphatic system.

B lymphocytes (B cells) are responsible for producing antibodies that bind to specific antigens on the surface of pathogens or abnormal cells. Antibodies mark these cells for destruction by other immune cells or by complement proteins. B cells also act as antigen-presenting cells that activate T cells .

T lymphocytes (T cells) are divided into two main types: T helper cells (Th) and T cytotoxic cells (Tc). Th cells secrete cytokines that stimulate the activity of other immune cells, such as B cells, macrophages, and NK cells. Th cells also help to regulate the immune response and prevent autoimmunity. Tc cells directly kill infected or abnormal cells by releasing perforin and granzymes that induce apoptosis. Tc cells also express death receptor ligands that trigger apoptosis in target cells .

NK cells share some features with both B and T cells, but they also have some unique characteristics. Unlike B and T cells, NK cells do not have antigen-specific receptors, which means they can recognize and kill a wide range of target cells without prior exposure or activation. NK cells can also kill target cells by degranulation or by expressing death receptor ligands, similar to Tc cells. However, NK cells also have inhibitory receptors that prevent them from killing normal cells that express self-MHC molecules .

NK cells can also interact with B and T cells in various ways. For example, NK cells can enhance the antibody production by B cells by providing cytokines and contact-dependent signals. NK cells can also cooperate with Tc cells to eliminate virus-infected or tumor cells by forming conjugates and exchanging cytotoxic granules. NK cells can also modulate the function of Th cells by producing cytokines that influence their differentiation and polarization.

Therefore, NK cells are closely related to other lymphoid cells like B and T lymphocytes, but they also have distinct roles and mechanisms in the immune system.

Natural killer cells are large, granular, and bone-marrow-derived lymphocytes . The granules found in the cytoplasm of the cell are azurophilic and are filled with hydrolytic and digestive enzymes . NK cells are larger in diameter than other similar lymphocytes . These lack the receptors found in other lymphocytes like T and B cells .

Natural Killer cells also exist in various shapes and express microvilli, especially in the area of effector-to-target contact . The granules in these cells consist of two distinct compartments. The outer compartment consists of the lysosome-associated phosphatase acid enzymes and trumetaphosphatase. The inner compartment consists of structural components and has no enzymatic activities associated with it.

During degranulation, a particular area within the cytoplasm forms multiple vacuole-like areas consisting of granules and some granular debris. The cytoplasm also contains other cytoplasmic organelles like mitochondria and polysomes. The nucleus is convoluted with distinct polarity against dense granules and pseudopodia.

The surface of natural killer cells consists of different activating and inhibitory receptors that recognize different membrane proteins . These receptors are responsible for regulating the function of NK cells and sensing the alterations of self cells caused by stress, infection, or malignancy .

Some of the common receptors expressed by NK cells are:

• CD56: A neural cell adhesion molecule that distinguishes NK cells from other lymphocytes .
• CD16: A low-affinity receptor for IgG that mediates antibody-dependent cell-mediated cytotoxicity (ADCC) .
• CD57: A marker of terminal differentiation and senescence of NK cells.
• NKp46: A natural cytotoxicity receptor (NCR) that recognizes viral hemagglutinins and tumor antigens .
• NKG2D: An activating receptor that binds to stress-induced ligands on infected or transformed cells .
• KIRs: Killer cell immunoglobulin-like receptors that bind to MHC class I molecules and modulate the cytotoxicity of NK cells .

Natural killer (NK) cells are a group of innate lymphoid cells that can rapidly respond to a wide variety of pathogens, such as viruses, bacteria, fungi, and parasites. NK cells can recognize and kill infected or stressed cells by using different receptors and mechanisms .

One of the main functions of NK cells is to mediate cytotoxicity against virus-infected cells and tumor cells. NK cells can detect the presence of viral antigens or stress-induced molecules on the surface of target cells and trigger the release of cytotoxic granules containing perforin and granzymes. Perforin forms pores on the target cell membrane, allowing granzymes to enter and induce apoptosis . NK cells can also induce cell death by expressing death receptor ligands, such as Fas ligand (FasL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), that bind to their corresponding receptors on the target cells and activate the caspase cascade.

Another important function of NK cells is to produce cytokines and chemokines that modulate the immune response and inflammation. NK cells can secrete interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), interleukin-5 (IL-5), interleukin-13 (IL-13), interleukin-8 (IL-8), macrophage inflammatory protein-1 beta (MIP-1β), and other factors that have various effects on other immune cells, such as macrophages, dendritic cells, T cells, and B cells . For example, IFN-γ enhances the antiviral and antitumor activity of macrophages and T cells, TNF-α promotes inflammation and tissue damage, IL-10 suppresses inflammation and immune activation, IL-5 and IL-13 stimulate eosinophil production and activation, IL-8 attracts neutrophils and other leukocytes to the site of infection, and MIP-1β inhibits HIV replication in macrophages .

NK cells can also cooperate with other immune cells to enhance their functions. For instance, NK cells can participate in antibody-dependent cellular cytotoxicity (ADCC), where they recognize antibodies bound to antigens on the target cells and kill them by using their Fc receptors . NK cells can also activate macrophages by producing IFN-γ and TNF-α, which increase their phagocytic and microbicidal abilities . Moreover, NK cells can interact with dendritic cells by exchanging signals through cell surface molecules or soluble factors, which can result in either activation or inhibition of both cell types .

Thus, NK cells are versatile immune effectors that can mount different responses against pathogens depending on the context and signals they receive. By killing infected or stressed cells and producing cytokines and chemokines, NK cells play a crucial role in innate immunity and influence adaptive immunity as well .

One of the main mechanisms by which NK cells kill target cells is through degranulation, which is the process of releasing cytotoxic molecules from secretory granules inside the NK cells. These molecules include perforin and granzymes, which can induce apoptosis or programmed cell death in the target cells.

Degranulation is triggered by the recognition of target cells by activating receptors on the surface of NK cells, such as CD16, which binds to antibodies that coat the target cells. This process is called antibody-dependent cellular cytotoxicity (ADCC).

When an NK cell forms an immunological synapse with a target cell, it undergoes a series of steps that lead to degranulation. These steps are:

• Formation of immunological synapse between the target cell and NK cell followed by a reorganization of the actin cytoskeleton.
• Polarization of microtubule-organizing center and secretory lysosome towards lytic synapse.
• Docking of secretory lysosome with the plasma membrane of NK cells.
• Fusion of secretory lysosome with the plasma membrane of target cells.

During degranulation, a protein called lysosome-associated membrane protein-1 (LAMP-1, CD107a) is transported from the granules to the cell surface and becomes accessible for antibody binding. This can be used as a marker for degranulation in NK cells.

The perforin released by NK cells forms pores on the membrane of target cells, allowing the entry of granzymes into the cytoplasm. Granzymes are serine proteases that activate caspases, which are enzymes that initiate a cascade of events leading to apoptosis.

Degranulation is a rapid and efficient way for NK cells to eliminate infected or abnormal cells without causing excessive inflammation or tissue damage. However, degranulation also requires local signaling and activation of receptors on both NK cells and target cells, which prevents unwanted killing of normal cells.

Besides their cytotoxic activity, NK cells also act as effector cells by producing and releasing various cytokines and chemokines that modulate the immune response against pathogens and tumors. Cytokines are small proteins that act as signaling molecules between cells, while chemokines are a subset of cytokines that induce chemotaxis (movement) of immune cells.

Some of the cytokines produced by NK cells include interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), interleukin-5 (IL-5), and interleukin-13 (IL-13). These cytokines have different effects on the immune system, such as enhancing the activation and differentiation of other immune cells, promoting inflammation, inhibiting viral replication, and regulating antibody production. For example, IFN-γ is a key cytokine that activates macrophages, dendritic cells, and T cells, and also stimulates the expression of major histocompatibility complex (MHC) molecules on target cells, making them more susceptible to recognition by NK cells and T cells . TNF-α is another important cytokine that induces apoptosis (cell death) of target cells, recruits inflammatory cells to the site of infection or tumor, and enhances the expression of adhesion molecules on endothelial cells . IL-10 is an anti-inflammatory cytokine that inhibits the production of pro-inflammatory cytokines by macrophages and dendritic cells, and also suppresses the proliferation and function of T cells . IL-5 and IL-13 are cytokines that are involved in allergic responses and parasitic infections, as they stimulate the production and activation of eosinophils, a type of granulocyte that can kill parasites and release inflammatory mediators .

Some of the chemokines produced by NK cells include interleukin-8 (IL-8), macrophage inflammatory protein-1 beta (MIP-1β), and monocyte chemoattractant protein-1 (MCP-1). These chemokines attract other immune cells to the site of infection or tumor, such as neutrophils, monocytes, macrophages, dendritic cells, and T cells . Chemokines also play a role in regulating the tissue distribution and trafficking of NK cells themselves, as they bind to specific receptors expressed on NK cell surface. For example, IL-8 binds to CXCR1 and CXCR2 receptors on NK cells and promotes their migration to inflamed tissues. MIP-1β binds to CCR5 receptor on NK cells and mediates their homing to lymphoid organs. MCP-1 binds to CCR2 receptor on NK cells and facilitates their recruitment to sites of tissue injury.

The effector immune response of NK cells through cytokines and chemokines is crucial for the clearance of pathogens and tumors, as well as for the coordination of innate and adaptive immunity. By releasing these molecules, NK cells can enhance their own cytotoxic activity, as well as stimulate other immune cells to mount a more effective response against the invaders. However, excessive or dysregulated production of cytokines and chemokines by NK cells can also cause adverse effects, such as tissue damage, inflammation, autoimmunity, or immunosuppression . Therefore, the balance between activating and inhibitory signals on NK cell surface is important for maintaining a proper effector immune response.

Natural killer cells are able to distinguish between normal and abnormal cells by using a balance of signals from activating and inhibitory receptors. The inhibitory receptors recognize MHC class I molecules that are expressed on the surface of healthy cells, but may be downregulated or altered in stressed, infected, or transformed cells . This mode of NK cell target interaction is known as "missing-self recognition".

The inhibitory receptors belong to two major families: the killer cell immunoglobulin-like receptors (KIRs) and the CD94/NKG2A heterodimers. The KIRs are a diverse group of receptors that recognize different HLA class I allotypes and have either two (KIR2D) or three (KIR3D) immunoglobulin-like domains. The CD94/NKG2A heterodimers are C-type lectin-like receptors that recognize HLA-E, a non-classical HLA class I molecule that presents peptides derived from the leader sequences of other HLA class I molecules.

The inhibitory receptors transmit negative signals to the NK cells through immunoreceptor tyrosine-based inhibition motifs (ITIMs) that recruit phosphatases like SHP-1 and SHP-2 upon ligand binding. These phosphatases dephosphorylate key signaling molecules involved in NK cell activation, such as Vav1, PLCγ, and LAT, and thus prevent the release of cytotoxic granules and cytokines.

The inhibitory receptors also play a role in the education and maturation of NK cells. During their development, NK cells acquire a repertoire of inhibitory receptors that match the self-MHC class I molecules expressed by the host. This process ensures that NK cells are tolerant to self-tissues and responsive to foreign or abnormal cells. The expression of inhibitory receptors also correlates with the functional competence of NK cells, as they acquire more cytotoxic potential and cytokine production capacity as they mature.

The inhibitory action of NK cells is essential for preventing unwanted damage to healthy cells and maintaining immune homeostasis. However, some pathogens and tumors may exploit this mechanism by upregulating MHC class I molecules or expressing ligands for inhibitory receptors to evade NK cell-mediated immunity. Therefore, strategies to block or modulate the inhibitory receptors may enhance the therapeutic potential of NK cells against various diseases.

NK cells are versatile lymphocytes that can perform various functions depending on the context and the signals they receive. Some of the functions of NK cells are:

• Cytolytic activity: NK cells can kill target cells by releasing cytotoxic molecules like perforin and granzymes, which induce apoptosis or programmed cell death. This function is important for eliminating virus-infected cells and tumor cells that have lost or downregulated their MHC I molecules .
• Antibody-dependent cell-mediated cytotoxicity (ADCC): NK cells can also recognize antibody-coated target cells through their CD16 receptor, which binds to the Fc portion of IgG antibodies. This triggers NK cell activation and degranulation, leading to target cell lysis. This function is important for enhancing the efficacy of some therapeutic antibodies against cancer .
• Cytokine production: NK cells can secrete various cytokines and chemokines that modulate the immune response and inflammation. For example, NK cells can produce IFN-γ, which activates macrophages and enhances antigen presentation and Th1 differentiation. NK cells can also produce TNF-α, which induces apoptosis of target cells and promotes inflammation. Other cytokines produced by NK cells include IL-10, IL-5, IL-13, IL-8, and MIP-1β .
• Immunoregulation: NK cells can interact with other immune cells and influence their functions. For example, NK cells can stimulate dendritic cell maturation and antigen presentation by releasing IFN-γ and TNF-α. NK cells can also cooperate with T cells and macrophages to clear intracellular pathogens by forming granulysin-expressing lymphocyte clusters. NK cells can also suppress the activation and proliferation of T cells by killing activated T cells or by producing IL-10 .
• Immunosurveillance: NK cells can patrol the body and detect abnormal or stressed cells that express stress-induced ligands or lack MHC I molecules. These include tumor cells, senescent cells, or infected cells. By eliminating these cells, NK cells prevent their proliferation and dissemination, and thus protect against cancer and chronic infections .
• Reproductive immunity: NK cells are abundant in the uterus during pregnancy, where they play a role in regulating placental development and fetal growth. Uterine NK cells are distinct from peripheral blood NK cells in that they have lower cytotoxicity and higher cytokine production. Uterine NK cells interact with fetal trophoblasts and maternal endothelial cells to promote angiogenesis, vascular remodeling, and nutrient transport. Uterine NK cells also secrete factors that prevent maternal immune rejection of the fetus.

In conclusion, NK cells are multifunctional lymphocytes that contribute to both innate and adaptive immunity. They have diverse roles in fighting infections, controlling tumors, regulating inflammation, and supporting pregnancy.

Natural killer (NK) cells are a vital component of the innate immune system that can rapidly respond to various pathogens and stressed cells. They have multiple functions that contribute to the protection and regulation of the host immunity. Some of these functions are:

• Cytolytic activity: NK cells can kill virus-infected cells, tumor cells, and other abnormal cells by releasing cytotoxic molecules like perforin and granzymes, or by engaging death receptors on the target cells .
• Cytokine production: NK cells can secrete various cytokines and chemokines that modulate the functions of other immune cells, such as macrophages, dendritic cells, T cells, and B cells . These cytokines can enhance the antiviral, antibacterial, and antitumor responses, as well as regulate the inflammation and immune tolerance.
• Antibody-dependent cell-mediated cytotoxicity (ADCC): NK cells can recognize antibody-coated target cells through their Fc receptor CD16 and exert cytotoxicity against them . This mechanism is important for the clearance of antibody-opsonized pathogens and tumor cells.
• Immunosurveillance: NK cells can patrol various tissues and organs and detect signs of cellular stress, such as the expression of stress-induced ligands or the loss of major histocompatibility complex (MHC) class I molecules . These signals indicate the presence of infection or transformation and trigger the activation of NK cells to eliminate the potential threat.
• Adaptive features: NK cells can display some characteristics of adaptive immunity, such as memory-like responses, clonal expansion, and increased longevity . These features enable NK cells to respond more efficiently and robustly to secondary exposures to the same or related antigens.
• Reproductive immunity: NK cells are abundant in the uterus during pregnancy and play a crucial role in ensuring a successful implantation and fetal development . They can modulate the maternal immune system to prevent rejection of the fetal allograft, as well as promote angiogenesis and placental growth.

In conclusion, NK cells are versatile and multifunctional lymphocytes that can sense and respond to various challenges in the host. They have both cytotoxic and regulatory roles that are essential for maintaining the homeostasis and integrity of the immune system. NK cells are also involved in several clinical applications, such as immunotherapy for cancer and viral infections. Therefore, understanding the biology and function of NK cells is important for advancing our knowledge and treatment of various diseases.

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