- Natural Killer (NK) cells are a type of cytotoxic lymphocyte and a key component of the innate immune system, crucial for antiviral defense and cancer surveillance.
- Unlike T and B cells, NK cells recognize and eliminate infected or malignant cells without prior sensitization, making them the body’s first line of defense against infections and cancer. This rapid response capability makes NK cells an attractive target for therapeutic development.
- NK cells originate from hematopoietic stem cells in the bone marrow, where they undergo early differentiation. Full maturation and functional development occur in the bone marrow and secondary lymphoid organs, such as the spleen and lymph nodes. Cytokines, including interleukin-15 (IL-15), are essential for their development, survival, and activation. They belong to the broader family of innate lymphoid cells (ILCs) and share a common progenitor with T and B cells but do not undergo the same antigen receptor gene rearrangement process.
- NK cells are primarily identified by surface expression of CD56 and absence of CD3 (a marker for T cells). Based on the density of CD56, NK cells are classified into two main subpopulations: CD56bright NK cells and CD56dim NK cells
- CD56bright NK cells (high CD56 expression, negative for CD16) are involved in cytokine production, while CD56dim NK cells (low CD56 expression, positive for CD16) are more cytotoxic and mediate target cell killing.
- NK cells function through a complex interplay of activating and inhibitory receptors. Healthy cells express MHC class I molecules that bind to inhibitory receptors on NK cells, preventing their attack. Infected or cancerous cells often downregulate MHC class I expression, reducing inhibitory signals and allowing NK cells to trigger cytotoxic activity. This “missing-self” hypothesis explains how NK cells distinguish between healthy and unhealthy cells.
- Upon activation, NK cells eliminate target cells through direct cytotoxicity (release of perforin and granzymes), death receptor pathways (expression of FasL and TRAIL, triggering apoptosis via death receptors), and antibody-dependent cellular cytotoxicity (ADCC) through engagement of CD16 receptor to kill antibody-coated target cells.
- In addition to cytotoxicity, NK cells produce cytokines and chemokines such as IFN-γ, TNF-α, and GM-CSF, which activate macrophages, dendritic cells, and T cells, enhancing antigen presentation and promoting inflammation. IFN-γ is particularly essential for macrophage activation, while TNF-α regulates immune responses and inflammation.
- NK cells contribute to both innate and adaptive immunity by modulating the immune response. NK cells constantly monitor tissues for infection or stress and are essential for controlling viral and bacterial infections, especially in the early stages before adaptive immunity is fully activated. Their ability to rapidly respond bridges innate and adaptive immunity, helping to contain viral spread until T cells can mount a more targeted response. NK cells are especially critical in combating infections such as herpesviruses, influenza, and HIV.
- NK cells play a key role in tumor immunosurveillance by targeting tumor cells that downregulate MHC class I or express tumor-associated antigens. They also mediate ADCC via CD16. However, tumors can evade NK cell detection by restoring MHC class I or expressing decoy molecules.
- NK cell activity is tightly regulated to prevent autoimmunity, with inhibitory receptors recognizing self-MHC I and a “licensing” process ensuring functional competence. In cancer immunity, NK cells target MHC I-deficient tumor cells, making them critical effectors in immune defense.
- NK cells are emerging as a promising tool in immunotherapy, particularly for cancer treatment. Strategies such as adoptive NK cell transfer, CAR-NK cell therapy, and NK cell engagers are being explored to enhance their antitumor activity.
- NK cells do not require patient-specific matching, making them ideal for off-the-shelf therapies.
- Cryopreservation facilitates NK cell banking, ensuring a readily available supply for clinical use.
- Beyond cancer, NK cells are being investigated for viral infections, autoimmune diseases, and regenerative medicine, where their immunomodulatory properties may support tissue repair. However, chronic infections and tumor-induced immunosuppression can lead to NK cell exhaustion, reducing their function.
- Approaches like checkpoint blockade therapy and cytokine stimulation aim to restore NK cell activity. Advances in NK cell engineering, including gene editing and cytokine modulation, are enhancing their therapeutic potential. Ongoing research focuses on optimizing NK cell-based treatments to improve efficacy and accessibility in clinical applications.
- Abbreviations:
- ADCC (antibody-dependent cellular cytotoxicity)
- MHC (Major histocompatibility complex)
- NK (Natural Killer) cells
- CAR (Chimeric Antigen Receptors)
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