The human body contains various types of immune cells that respond to different pathogens, swiftly clearing them to prevent threats to health. Natural Killer Cells (NK cells) are integral components of the body’s innate immune system, crucial for combating infections and malignant tumors.
Since their discovery over forty years ago, NK cells have been the focus of immunologists worldwide. This is because NK cells possess unique, innate abilities. They can recognize and eliminate abnormal cells in a process that doesn’t require prior learning, unlike other immune cells such as T cells and B cells, which need a learning process to recognize antigens.
The distinct properties of NK cells make them essential “killers” in the immune system. They can rapidly identify infected or mutated cells without waiting for activation by other immune cells. This innate killing ability makes NK cells highly effective in swiftly responding to pathogens and clearing abnormal cells.
1.Natural Killer Cells (NK Cells) in Biology
NK cells are a specialized type of immune cell in the body, originating from the bone marrow and belonging to the lymphocyte family. They primarily differentiate from hematopoietic stem cells in the bone marrow and possess the ability to inhibit the invasion of viruses and bacteria and eliminate abnormal cells within the body, including those that are cancerous, diseased, or senescent. Identified by the surface markers CD56 and CD16, NK cells do not express T-cell receptors (TCRs) and CD3, distinguishing them structurally from T cells and B cells.
Unlike these immune cells, NK cells do not undergo antigen recognition through somatic cell recombination. When there is an imbalance in stem cell differentiation, lymphocyte production may decrease while bone marrow cell production may increase, potentially weakening the body’s defense against external pathogens. Bone marrow cells typically resist pathogen invasion by triggering inflammatory responses. However, excessive or chronic inflammatory responses may also pose risks to health.
The ability of NK cells to identify and eliminate abnormal cells relies on a series of complex activating and inhibitory receptors. Key activating receptors include NKG2D and NKp46, which bind ligands on the surface of target cells, activating NK cell cytotoxic functions. Simultaneously, inhibitory receptors such as killer cell immunoglobulin-like receptors (KIRs) and CD94/NKG2A can prevent NK cell activation, thereby protecting healthy cells from attack.
The balance between these signaling messages determines whether NK cells are activated or inhibited, enabling them to effectively and specifically identify and eliminate target cells. This capability underscores the crucial role of NK cells in the body’s immune system, particularly in the rapid response to pathogens and clearance of abnormal cells.
2.Functions of Natural Killer Cells (NK Cells)
Natural Killer (NK) cells are vital members of the body’s immune system, primarily responsible for combating virus-infected cells and tumor cells, providing rapid and nonspecific immune support. When NK cells encounter target cells, they inspect the surface for the presence of major histocompatibility complex class I (MHC-I) molecules. Under normal circumstances, healthy cells express MHC-I molecules, which bind to inhibitory receptors on NK cells, thereby preventing their activation. However, infected or transformed cells often downregulate MHC-I expression to evade recognition by T cells, which also makes them targets for NK cell attack.
Once activated, NK cells<1> release a range of cytotoxic mechanisms, including the release of perforins and granzyme, which induce apoptosis through death receptor signaling. Additionally, NK cells secrete cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), promoting inflammatory responses further. This multifaceted mechanism ensures the rapid eradication of target cells while minimizing collateral damage to surrounding tissues. Consequently, NK cells play a crucial role in maintaining the stability of immune balance within the body’s immune system.
NK cells are referred to as “killer cells” due to their distinctiveness in eliminating pathogens compared to other cells. While other cells require immune stimulation over a period, NK cells initiate an attack as soon as they detect foreign entities such as cancer cells. Therefore, NK cells are part of the innate immune system.
3.Regulation of NK Cell Activity
The function of NK cells in the body is tightly regulated by complex interactions involving target cells, cytokines, and other immune cells. Cytokines such as interleukin-12 (IL-12), IL-15, and IL-18 play critical roles in the activation, proliferation, and maintenance of NK cells. Particularly, IL-15 is indispensable for the development and homeostasis of NK cells. Additionally, interactions with dendritic cells (DCs) and macrophages shape NK cell responses by providing co-stimulatory signals and cytokine cues.
Furthermore, NK cells exhibit a phenomenon known as “education” or “permission.” This means that during their development and differentiation in the bone marrow, NK cells undergo functional maturation and acquire self-tolerance. This process is crucial for maintaining the balance of the body’s immune system. Through this self-tolerance mechanism, NK cells can maintain tolerance to healthy body tissues while retaining the ability to attack abnormal or infected cells.
Therefore, NK cells play a critical role in the immune system, coordinating and enhancing immune responses through close interactions with other immune cells and cytokines. This intricate regulatory mechanism ensures the effective clearance of pathogens and tumor cells while minimizing damage to self-tissues. Overall, the function and regulation of NK cells are essential components in maintaining the health and functionality of the body’s immune system while preserving the ability to eliminate abnormal cells.
4.The Therapeutic Potential of NK Cells
Due to their unique and specific characteristics, NK cells have emerged as promising therapeutic options for treating tumors and infectious diseases. Clinical trials utilizing expanded autologous NK cells have demonstrated efficacy against hematological malignancies and solid tumors. These cells can rapidly identify and destroy tumor cells while causing relatively minimal damage to normal tissues.
In addition to the application of natural NK cells, gene engineering technologies have opened up new therapeutic avenues. For example, researchers have found that chimeric antigen receptor (CAR) NK cells, by enhancing their ability to recognize specific tumor antigens, improve the therapeutic effects against tumors. This approach has shown promising results in clinical settings, paving the way for novel prospects in tumor therapy.
Furthermore, utilizing NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) is another effective therapeutic strategy. By coupling antibodies with NK cells, the killing effect on tumor cells can be enhanced while reducing damage to normal tissues, as evidenced in both experimental and clinical studies.
In the field of regenerative medicine, NK cells can be mass-cultured and activated ex vivo before being reintroduced into the body to enhance immune function. Common causes of decreased NK cell activity include aging, excessive stress, inadequate sleep, imbalanced diet, and medication effects. While lifestyle improvements can enhance activity to some extent, the rate of aging remains relatively rapid. Therefore, current NK cell therapies typically involve extracting the patient’s own cells for ex vivo cultivation to enhance their activity.
NK cells primarily exist in the peripheral blood system of the body, so in conventional NK immunotherapy, blood is first extracted from the patient. Subsequently, NK cells are isolated in the laboratory and supplemented with specific cytokines. After approximately 14 days of cultivation, NK cells can proliferate and become activated in large quantities. Through NK cell therapy, blood collected from the patient is activated with hormones and then reintroduced into the body. Since the patient’s own cellular tissues are used, there are usually no significant side effects.
Furthermore, combination therapy strategies are extensively researched to further enhance the functionality of NK cells. For example, combining checkpoint inhibitors and cytokine-based immune modulation can increase the persistence and efficacy of immune responses, thereby improving therapeutic outcomes.
5.Conclusion
The unique and specific nature of NK cells, coupled with diverse therapeutic strategies, make them ideal candidates for treating tumors and infectious diseases through harnessing the body’s immune system. Through NK cell therapy, blood collected from the patient is activated with hormones and then reintroduced into the body. Since the patient’s own cellular tissues are used, there are usually no significant side effects. Both domestically and internationally, restrictions on regenerative medicine and stem cell applications are gradually being relaxed.
Therefore, many individuals are considering storing stem cells for potential future autologous medical needs. With the continuous advancement of scientific technology and progress in clinical research, it is believed that NK cell therapy <2>will continue to achieve more breakthroughs in the future, providing patients with better treatment outcomes and quality of life.
6.Reference
1.Natural Killer Cell,NK，CHANGHUA CHRISTIAN HOSPITAL，2024.03.04
2.Tumors evade immune cytotoxicity by altering the surface topology of NK cells，Nature Immunology，