Killer cells, also known as cytotoxic T cells, are a critical part of the immune system and help protect the body against infection and disease. They are a type of white blood cell that directly attacks and kills infected cells, cancer cells, and cells that are damaged in other ways. Understanding killer cells and how they function provides important insight into the complex workings of the immune system.
What are killer cells?
Killer cells, or cytotoxic T lymphocytes, are a subset of T cells that directly kill infected, damaged, or cancerous body cells. They are part of the adaptive immune system and play a critical role in cellular immunity. Killer cells differentiate from naive T cells after becoming activated by interacting with an antigen presented by an antigen-presenting cell.
Once activated, killer cells proliferate rapidly and start seeking out target cells that express the same antigen that activated them. This allows them to selectively identify and kill cells that have been infected by pathogens or have become cancerous while leaving healthy cells unharmed.
Killer cells induce programmed cell death, or apoptosis, in target cells. This process helps limit the spread of intracellular infections and prevents the growth and proliferation of cancerous cells. Killer cells are constantly circulating in the bloodstream and lymph system, surveying the body for the presence of foreign or abnormal antigens.
Mechanism of action
Killer cells use a multi-step process to induce apoptosis in target cells:
1. The killer cell first binds to the target cell through an antigen-specific interaction. This activates the killer cell.
2. The killer cell releases perforin and granzyme proteins that will induce apoptosis in the target cell. Perforin forms pores in the target cell’s membrane allowing the granzymes to enter.
3. The granzymes trigger apoptosis through a series of enzymatic reactions that activate the caspase cascade within the target cell. This leads to DNA degradation and cell death.
4. The killer cell releases cytokines like interferon-gamma to recruit and activate other immune cells like macrophages to the site. The macrophages will engulf and digest the remains of the dead target cell.
This targeted process allows killer cells to eliminate dangerous or abnormal cells without causing excessive damage to healthy tissue. It is a key mechanism the adaptive immune system uses to protect against intracellular pathogens and emerging cancer cells.
Major Types of Killer Cells
There are two major populations of killer cells that make up the cytotoxic lymphocyte group:
Cytotoxic T Cells
Cytotoxic T cells, also known simply as killer T cells, arise from T cell precursors that develop in the thymus gland. They express T cell receptors that can recognize protein fragments from pathogens or abnormal cells presented on MHC I molecules.
These cells circulate through the blood, lymph nodes, and tissues surveying for the presence of their specific antigen. When they encounter their antigen, they become activated, proliferate rapidly, and kill cells expressing that antigen through directed exocytosis of perforin and granzymes.
Cytotoxic T cells are a critical component of the cell-mediated adaptive immune response against intracellular viral infections and cancerous cells. They provide targeted, antigen-specific elimination of dangerous or infected cells in the body.
Natural Killer Cells
Natural killer (NK) cells are cytotoxic lymphocytes that can induce apoptosis in target cells without prior antigen exposure. They arise from hematopoietic stem cells in the bone marrow and circulate in a resting state, becoming activated by cytokines or through missing “self” signals.
NK cells express activating and inhibitory receptors on their surface. The balance of signaling between these receptors determines if the NK cell will be triggered. Cells that lack proper MHC I molecules, indicating missing “self,” are targeted for destruction.
NK cells contain cytotoxic granules preformed in their cytoplasm, allowing them to induce apoptosis in target cells very rapidly after becoming activated. This provides early innate immune protection against infections and cancer until antigen-specific cytotoxic T cells can be activated.
Mechanisms of Killing
Killer cells employ two major cytolytic mechanisms to induce apoptosis in target cells:
Granule Exocytosis Pathway
This is the primary killing mechanism used by cytotoxic T cells and NK cells. It involves directed release of perforin and granzyme-containing granules at the immunological synapse with a target cell:
– Perforin forms pores in target cell membrane allowing entry of granzymes
– Granzymes trigger apoptosis by activating caspases and inducing DNA fragmentation
– Granzymes also process cytokines to recruit other immune cells
This pathway induces apoptosis rapidly but is somewhat nonspecific beyond recognizing the target antigen.
Death Receptor Pathway
This mechanism relies on triggering apoptosis by engaging death receptors on the target cell surface:
– Killer cell expresses Fas ligand or TNF-related apoptosis-inducing ligand (TRAIL)
– These bind to Fas or TRAIL receptors on target cell membrane
– Receptor aggregation initiates apoptotic signaling cascades within target cell
This provides a more targeted, slower method of inducing cell death. It complements the faster, less specific granule exocytosis pathway.
Perforin and Granzymes
Perforin and granzymes are key effector molecules stored in the cytotoxic granules of killer cells and released during granule exocytosis:
– Perforin: creates pores in target cell membrane for entry of granzymes
– Granzyme A: cleaves proteins vital for DNA repair and replication
– Granzyme B: activates caspase cascade to induce apoptosis
– Granzyme M: degrades cytoskeleton proteins
The combined activity of perforin and granzymes rapidly overwhelms the target cell and induces programmed cell death within minutes. This prevents further spread of intracellular pathogens or growth of cancerous cells.
Killer Cell Activation
Killer cells must undergo activation before they can exhibit cytotoxic functions. This occurs through different mechanisms for NK cells and cytotoxic T cells.
NK Cell Activation
NK cells become activated by the following mechanisms:
– Binding of ligands to activating NK receptors
– Lack of MHC I molecules on cell surface (missing “self” signal)
– Stimulation by cytokines like IL-2, IL-12, IL-15, and interferon-alpha
Activated NK cells upregulate perforin and granzyme expression and become primed for cytotoxicity.
Cytotoxic T Cell Activation
Naive cytotoxic T cells are activated by:
– Interaction between their T cell receptor and specific antigen peptide presented by an antigen-presenting cell via MHC I
– Co-stimulation through CD28 and other co-receptors
– Stimulation by cytokines like IL-2 and interferon-gamma
This triggers clonal expansion and differentiation into effector cytotoxic T cells ready to kill target cells displaying the same antigen.
Targeting Cancer Cells
Killer cells play an important role in immune surveillance and destruction of cancerous cells through the following mechanisms:
Detecting Cancer Antigens
– Mutations in cancer cells create novel protein antigens
– These antigens are degraded into peptides and presented on MHC I
– Killer cells detect these cancer antigens and become activated
Killing Cancer Cells
– Activated killer cells release perforin/granzymes or express death ligands
– These induce apoptosis in cancer cells expressing the antigen
– Cancer cells are eliminated before they can proliferate further
Remembering Cancer Antigens
– Exposure to cancer antigens causes clonal expansion of killer cells
– Some become long-lived memory cells that confer lasting immunity
– Memory cells mount rapid responses to destroy emerging cancer cells
These mechanisms help provide constant immune surveillance against cancer development and growth.
Challenges in Cancer Defense
– Cancer cells exhibit reduced MHC I expression to evade killer cells
– Tumor microenvironments suppress killer cell activity
– Cancer cells acquire mutations that disrupt apoptotic signaling
– Clonal deletion or anergy of high avidity killer cells
Strategies to augment the cancer-killing capacity of killer cells are an area of active research for immunotherapy.
Evading Killer Cell Detection
Though killer cells play a critical protective role, some pathogens and cancer cells have evolved mechanisms to avoid detection and killing:
Viral Evasion Strategies
– Synthesis of MHC I homologs that killer cells cannot detect
– Production of proteins that impair antigen processing and presentation
– Inhibition of interferon signaling important for antiviral defense
– Induction of inhibitory receptor ligands on infected cells
Cancer Cell Evasion Strategies
– Downregulation of MHC I to become “missing self”
– Secretion of immunosuppressive cytokines like TGF-beta and IL-10
– Recruitment of regulatory T cells that suppress killer cell activity
– Expression of PD-L1 which inhibits cytotoxicity upon binding PD-1
– Metabolic changes that inhibit immune cell function in tumor microenvironment
Finding ways to counter these evasion mechanisms is an important area of research for improving immunotherapy outcomes.
Killer Cell Deficiencies
Defects in killer cell development or function can lead to immune system disorders:
Primary Immunodeficiencies
– Severe combined immunodeficiency (SCID) – lack of T cells including killer cells
– X-linked lymphoproliferative disease – underactive NK and killer T cells
Acquired Immunodeficiencies
– HIV infection – depletion of CD4+ helper T cells impairs killer cell activity
– Post-transplant lymphopenia – immunosuppressants reduce killer cells
Consequences
– Increased risk of viral infections like Epstein-Barr virus or cytomegalovirus
– Higher rate of cancer development
– Overall mortality is significantly increased
Restoring proper killer cell numbers and function through hematopoietic stem cell transplants or gene therapy can be curative.
Therapeutic Potential
The potent, targeted cytotoxicity of killer cells has sparked substantial interest in their therapeutic potential:
Adoptive Cell Transfer
– Isolate killer cells from patient and expand ex vivo
– Engineer cells to express chimeric antigen receptors or high avidity TCRs
– Transfuse engineered killer cells back into patient
This provides a large population of highly active killer cells targeting the patient’s cancer cells. Significant clinical successes have been achieved, especially against certain blood cancers.
Checkpoint Inhibitors
– Antibodies targeting PD-1, PD-L1, CTLA-4
– Block inhibitory interactions to enhance killer cell activity against cancer
– Useful for augmenting endogenous anti-tumor immunity
The clinical use of checkpoint inhibitors has led to major advances in cancer immunotherapy.
Cytokine Therapy
– Administration of IL-2 promotes killer cell activation
– IL-15 stimulates NK cell and cytotoxic T cell proliferation
– IFN-alpha has immunostimulatory effects on killer cell function
Cytokine regimens can help boost anti-cancer immunity. Toxicity at high doses remains a challenge.
Overall, killer cells remain a promising target for immunotherapy given their natural ability to elicit potent, targeted immune responses against abnormal cells. Further research will help fulfill their therapeutic potential against cancer and other diseases.
Conclusion
Killer cells like cytotoxic T lymphocytes and natural killer cells play indispensable roles in protecting the body by directly inducing apoptosis in infected, damaged, or cancerous cells. Their ability to selectively eliminate dangerous cells makes them invaluable for cellular immunity against intracellular pathogens and abnormal tissue growth. Malfunctions in killer cell development or activity lead to immunodeficiency and increased susceptibility to infectious disease and cancer.
Research continues to uncover new insights into killer cell biology and how to therapeutically augment their functions against cancer. In the future, techniques to harness the cytotoxic capabilities of killer cells may provide more effective immunotherapies leading to improved clinical outcomes and cures for patients suffering from life-threatening illnesses.