Types of cytotoxicity and the role of myeloid cells
Myeloid cells use several different strategies to neutralize threats, each employed depending on the type of pathogen.
- Phagocytosis. This is classical intracellular digestion. Primarily the task of monocytes and macrophages—they are referred to as "professional" phagocytes. To a moderate extent, the ability to engulf particles is also characteristic of eosinophils, basophils, and mast cells.
- Extracellular cytolysis. This pathway is critically important for anti-parasitic and anti-tumor defense. The main effectors here are eosinophils and neutrophils, which release their contents outward.
- Contact-dependent cytolysis. The third type of myeloid cytotoxicity. Its targets are pathogens directly, as well as host cells that have already been infected by them.
Stages of contact establishment
A mandatory prerequisite for initiating contact-dependent cytolysis is close apposition between the effector cell and the target cell. This process is strictly regulated and occurs in two consecutive stages.
1. Nonspecific adhesion At this stage, initial firm mutual sticking of the cells to each other is ensured.
- On the surface of the myeloid cell, integrin molecules perform this task. Beta2-integrin LFA-1 is predominantly involved.
- Molecules of the immunoglobulin superfamily bind to them on the target cell surface, primarily ICAM-1 and ICAM-2 receptors.
2. Specific receptor recognition Following primary attachment, the myeloid cell must confirm that the encountered cell is indeed a target. This occurs through the recognition of opsonins on the surface of the infected cell.
- Ligands (on the target): Fc regions of IgG class antibodies, as well as fragments of complement system components (e.g., the iC3b protein), act as specific labels.
- Receptors (on the effector): Myeloid cells use Fc receptors to recognize antibodies. The Fc-gamma-RI receptor is expressed on macrophages and activated cells, whereas Fc-gamma-RIIA and Fc-gamma-RIII are present on all myeloid lineages. Corresponding CR receptors are used for complement recognition.
Killing mechanisms: transmission of the lethal signal
As soon as firm specific contact is established, the myeloid cell transmits a lethal signal to the target cell, which inevitably leads to apoptosis. Although the exact molecular mechanisms of this killing are still being studied, the involvement of three main pathways has been proven:
- Phagolysosome exocytosis. The effector releases toxic substances directly into the intercellular contact zone. The efficiency of this release is significantly enhanced precisely due to close preliminary adhesion.
- Cytokine secretion. The myeloid cell secretes tumor necrosis factor alpha (TNF-alpha). This cytokine binds to the TNFRI receptor on the target surface, triggering a death cascade.
- Membrane apoptosis inducers. The death signal can be transmitted via direct contact of membrane molecules—Fas ligand and TRAIL—with their specialized receptors on the target (Fas receptor, DR3, DR4).
Note: There is also a granzyme-mediated killing pathway, in which toxic enzymes are delivered inside the target. However, for myeloid cells, this mechanism is unlikely. It requires the highest specialization, characteristic only of lymphoid cells (natural killer cells and cytotoxic T lymphocytes).
Features of contact-dependent cytolysis
A crucial role in contact-dependent cytolysis is played by so-called "armed" macrophages. These are a special variety of already activated cells on whose surface antibodies are pre-fixed, ready to instantly recognize a threat.
Despite the complexity of the process, contact-dependent cytolysis is not the primary effector defense mechanism for myeloid cells. This is due to their biological functional features and the objective needs of the organism. Nature has assigned other priority tasks to the myeloid lineage, primarily large-scale phagocytosis and the initiation of inflammation.
Briefly: answers to topical questions
What toxic substances are released by myeloid cells during phagolysosome exocytosis?
During phagolysosome exocytosis, myeloid cells release various toxic substances into the extracellular space. The main degranulation products include:
- Nitric oxide derivatives (NO)—exhibit pronounced cytotoxic effects.
- Oxidative burst products (O2-, H2O2)—reactive oxygen species generated de novo.
- Acid hydrolases—enzymes active at low pH values.
- Lysosomal enzymes—ensure extracellular digestion of cells and their components.
These substances are released directly into the contact zone with the target, ensuring extracellular cytolysis.
How does the killing mechanism of myeloid cells differ from the cytotoxicity of NK cells and T lymphocytes?
The main difference lies in the fact that the delivery of granzymes into the target cell is unlikely for myeloid cells, whereas NK cells and cytotoxic T lymphocytes are characterized by the perforin-granzyme pathway. Myeloid cells utilize phagolysosome exocytosis, cytokine secretion such as TNFα, and membrane apoptosis inducers including Fas ligand and TRAIL. NK cells and cytotoxic T lymphocytes utilize perforin-granzyme and Fas-dependent cytolysis pathways.
Which enzymes and molecules ensure the intracellular digestion of pathogens during phagocytosis?
Intracellular digestion of pathogens in phagolysosomes is ensured by a complex of enzymes and bactericidal molecules. The main factors include:
- Reactive oxygen and nitrogen species (O2-, H2O2, NO)—highly reactive radicals and ions.
- Acid hydrolases—myeloperoxidase, 5'-nucleotidase, $\beta$-arylsulfatase, $\beta$-glucuronidase, acid glycerophosphatase, and glycosidases.
- Cationic proteins—serprocidins (cathepsin G, elastase, azurocidin), lysozyme, and lactoferrin.
- Bactericidal peptides—$\alpha$ and $\beta$ defensins, cathelicidins.
- Alkaline phosphatase—an enzyme of specific granules.
The main function of these substances is the degradation of killed microorganisms.
To memorize the contact stages, imagine a checkpoint security check: first, cells "hold hands" (nonspecific adhesion via LFA-1 and ICAM), and then the macrophage "checks the target's documents" (specific recognition of opsonins via Fc and CR receptors).
Class and exam questions
Is contact-dependent cytolysis the main weapon of myeloid cells?
No, contact-dependent cytolysis is not their main effector mechanism. The primary defense reaction of monocytes and macrophages remains classical phagocytosis.
What are "armed" macrophages?
These are activated macrophages on whose surface antibodies are pre-fixed, significantly accelerating and facilitating specific recognition of the target during cytolysis.
Can macrophages kill targets using granzymes?
This is extremely unlikely. The use of granzymes requires high cellular specialization and is a hallmark of natural killer (NK) cells and cytotoxic T lymphocytes.
What else to study on this topic
- Structure and functions of adhesion molecules: integrins (LFA-1) and the immunoglobulin superfamily (ICAM)
- Detailed classification of myeloid cell Fc receptors
- Mechanisms of extracellular cytolysis in anti-parasitic immunity
- Molecular apoptosis cascade upon activation of Fas receptors and DR3/DR4 receptors
- The role of the complement system and CR receptors in opsonization
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