Natural killer (NK) cells are a type of white blood cell that play a major role in the innate immune system. They survey the body for any abnormal or infected cells and initiate a rapid immune response to destroy them. There are two main types of natural killer cells: cytotoxic NK cells and cytokine-secreting NK cells.
Cytotoxic NK Cells
Cytotoxic NK cells are the classical NK cells that kill tumor cells and virus-infected cells directly. They make up around 90% of all circulating NK cells in the body. Cytotoxic NK cells contain cytotoxic granules in their cytoplasm filled with proteins like perforin and granzymes. When an NK cell encounters an abnormal cell, it releases these cytotoxic granules onto the target cell. The granules essentially punch holes in the target cell’s membrane, causing it to die via apoptosis. This direct killing mechanism enables a swift immune response against potentially dangerous cells in the body.
Some key features of cytotoxic NK cells:
- Express CD56 but lack CD16 receptors
- Contain cytotoxic granules
- Kill abnormal cells directly by releasing granules
- Make up ~90% of circulating NK cells
- Crucial for immediate immune response against tumors and infections
Mechanism of Cytotoxic NK Cells
Cytotoxic NK cells survey all cells in the body via their surface receptors. Normal healthy cells display major histocompatibility complex (MHC) class I molecules on their surface, which bind to inhibitory receptors on the NK cell and prevent it from attacking. Abnormal or infected cells often downregulate MHC class I expression to evade detection by cytotoxic T cells.
However, this loss of MHC class I also leads to a loss of engagement with the inhibitory NK cell receptors. The NK cell recognizes the lack of MHC-I as a sign of abnormality and becomes activated. Activating receptors on the NK cell then bind to stress ligands that are upregulated on abnormal cells, triggering release of the cytotoxic granules.
The granules contain perforin, granzymes, and granulysin proteins. Perforin forms pores in the target cell membrane, allowing entry of the granzymes which trigger apoptosis. This mechanism enables cytotoxic NK cells to rapidly distinguish abnormal cells and initiate cell death.
Role of Cytotoxic NK Cells
Cytotoxic NK cells play a vital role in the following immune processes:
- Cancer immunosurveillance – Constantly survey for tumor cells and initiate direct killing. Cancer cells often downregulate MHC-I as an evasion tactic.
- Viral infections – Kill virus-infected cells by detecting lack of MHC-I and stress ligands.
- Bacterial infections – Respond to common bacterial components and cytokines by killing infected cells.
- Transplant rejection – Powerful cytotoxicity against foreign cells lacking host MHC-I, hence manage NK cell activity during transplants.
- Pregnancy – Cytotoxicity against abnormal placental cells expressing reduced MHC-I.
Overall, cytotoxic NK cells provide a rapid first line of defense through their direct cytolytic activity, holding threats at bay until antigen-specific T cells can be activated.
Cytokine Secreting NK Cells
The second subset of NK cells are the cytokine secreting NK cells. Rather than directly killing cells, these NK cells have an immunoregulatory role by secreting various cytokines and chemokines. They make up the other ~10% of circulating NK cells.
The main cytokine produced by these NK cells is IFN-gamma, a proinflammatory cytokine that activates macrophages and dendritic cells. Some key features of cytokine secreting NK cells:
- Express CD56 but also express CD16 receptors
- Lack cytotoxic granules
- Secrete cytokines like IFN-gamma, TNF-alpha, GM-CSF
- Make up ~10% of circulating NK cells
- Stimulate and regulate wider immune response
Mechanism of Cytokine Secreting NK Cells
Like cytotoxic NK cells, cytokine secreting NK cells also detect abnormal cells via lack of MHC-I engagement. However, instead of directly killing cells, they secrete cytokines like IFN-gamma upon activation. IFN-gamma has potent immunostimulatory effects:
- Activates macrophages – Stimulates phagocytosis, production of toxic reactive oxygen species (ROS)
- Stimulates dendritic cells – Enhances antigen presentation to T cells
- Increases expression of MHC molecules to improve antigen presentation
- Promotes IgG2a antibody class switching in B cells
- Recruits other immune cells like neutrophils to site of inflammation
By secreting IFN-gamma and other cytokines, these NK cells play a crucial role in orchestrating a wider immune response against pathogens and tumors. They help stimulate and regulate both innate and adaptive immunity.
Role of Cytokine Secreting NK Cells
Cytokine secreting NK cells are important in:
- Viral infections – Secrete IFN-gamma to activate dendritic cells and macrophages.
- Bacterial infections – Proinflammatory cytokines recruit and stimulate other immune cells.
- Cancer – IFN-gamma activation of dendritic cells promotes anti-tumor adaptive immunity.
- Pregnancy – IFN-gamma helps regulate placentation and uterine vascular remodeling.
- Autoimmunity – Aberrant NK cell cytokine secretion can promote autoimmune inflammation.
While they have less direct cytotoxic function, cytokine secreting NK cells are vital for coordinating the optimal immune response to threats via cytokine signaling.
Comparison of the Two NK Cell Subsets
Here is a table summarizing the key differences between the two main natural killer cell subsets:
| Feature | Cytotoxic NK Cells | Cytokine Secreting NK Cells |
|---|---|---|
| Proportion of total NK cells | ~90% | ~10% |
| Surface receptors | CD56+, CD16- | CD56+, CD16+ |
| Cytotoxic granules | Present | Absent |
| Main action | Direct killing of abnormal cells | Secretion of cytokines like IFN-gamma |
| Key roles | Cancer immunosurveillance, viral infections, transplant rejection | Stimulate innate and adaptive immunity against infections and cancer |
In summary, while both subsets play an important role in immune defense, cytotoxic NK cells specialize in the direct elimination of threats, while cytokine secreting NK cells coordinate the wider immune response through cytokine signaling.
Development of Natural Killer Cells
NK cells arise from hematopoietic stem cells (HSCs) in the bone marrow, alongside other white blood cells. They go through distinct stages of development and maturation before becoming fully functional NK cells.
Key Stages of NK Cell Development
The development of NK cells from HSCs involves the following key stages:
- Hematopoietic stem cell – Pluripotent HSCs in the bone marrow give rise to the myeloid and lymphoid lineages.
- Early NK cell precursor – Precursors commit to the NK cell lineage and acquire some NK receptors.
- Immature NK cell – Immature NK cells leave the bone marrow and enter circulation.
- Mature NK cell – Immature NK cells complete final maturation steps in peripheral tissues into fully functional cytotoxic or cytokine secreting NK cells.
This developmental pathway is coordinated by the sequential expression of specific transcription factors and surface receptors at each stage.
Key Transcription Factors in NK Cell Development
Development of NK cells from HSCs relies on the regulated expression of certain transcription factors:
- PU.1 – Initiates NK cell commitment from HSCs
- E4BP4 – Essential for early NK precursor stage
- Eomes – Drives maturation of immature NK cells
- T-bet – Promotes final maturation steps into mature NK cells
In addition to these core transcription factors, epigenetic changes and signaling from supporting cells in the bone marrow microenvironment also regulate NK cell development.
Surface Receptors Expressed During NK Cell Maturation
The stage of NK cell maturation can be identified by surface receptor expression:
- Early precursors – CD34+, CD117+, CD94-
- Immature NK cells – CD56+, CD16-
- Mature cytotoxic NK cells – CD56+, CD16-
- Mature cytokine secreting NK cells – CD56+, CD16+
The progressive gain and loss of surface receptors guides the step-wise development of NK cells from HSCs.
Conclusion
Natural killer cells play a critical early role in immune defense through their rapid innate responses. There are two main functional subsets – cytotoxic NK cells that directly kill abnormal cells, and cytokine secreting NK cells that stimulate wider immune activity through cytokines like IFN-gamma. Both types arise from hematopoietic stem cells and undergo a carefully orchestrated developmental pathway to acquire their specialized functions. Understanding the biology of natural killer cells provides key insights into harnessing their anti-tumor and anti-viral activity.