Cell-mediated cytotoxicity is a crucial immune process where effector cells directly kill target cells, such as virus-infected cells, cancer cells, or foreign cells. This direct killing is distinct from antibody-mediated immunity (humoral immunity), which primarily uses antibodies to neutralize pathogens or mark them for destruction.
The primary mechanisms of cell-mediated cytotoxicity involve different types of effector lymphocytes and other immune cells. The two main types are:
- Cytotoxic T Lymphocyte (CTL)-Mediated Killing
- Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
Let's explore these mechanisms in detail.
Mechanisms of Cell-Mediated Cytotoxicity
Cell-mediated cytotoxicity relies on effector cells identifying and eliminating specific target cells through cell-to-cell contact.
1. Cytotoxic T Lymphocyte (CTL)-Mediated Killing
Cytotoxic T lymphocytes (CTLs), also known as cytotoxic T cells or CD8+ T cells, are a primary effector cell type in cell-mediated immunity. They are particularly important for clearing intracellular pathogens like viruses and eliminating abnormal cells, including cancer cells.
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Recognition: CTLs recognize target cells through the interaction between their T-cell receptor (TCR) and peptide antigens presented on the target cell surface by Major Histocompatibility Complex (MHC) Class I molecules. This interaction is highly specific.
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Activation & Conjugate Formation: Upon recognition and activation (often requiring co-stimulatory signals), the CTL forms a stable junction, called the immunological synapse, with the target cell.
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Killing Pathways: CTLs use two main pathways to induce apoptosis (programmed cell death) in the target cell:
- Perforin-Granzyme Pathway: CTLs release cytotoxic proteins from granules stored within their cytoplasm. Perforin creates pores in the target cell membrane, allowing granzymes (serine proteases) to enter the cell. Granzymes then activate caspases, a family of enzymes that dismantle the cell from within.
- Fas Ligand (FasL)-Fas Pathway: CTLs express FasL on their surface, which binds to the Fas receptor (also known as CD95) on the target cell surface. This binding triggers a signaling cascade inside the target cell that activates caspases and initiates apoptosis.
Once the target cell is eliminated, the CTL can detach and move on to find and kill other infected or abnormal cells.
2. Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
ADCC is another significant mechanism where effector cells are directed to kill target cells via antibodies. While involving antibodies (components of humoral immunity), the cytotoxic action is performed by the effector cell, classifying it under cell-mediated cytotoxicity.
As the name indicates, the Ab-dependent cell-mediated cytotoxicity (ADCC) mechanism is governed by effector cells (e.g., natural killer cells, eosinophils, macrophages, or neutrophils of the humoral immune system) that lead to the lysis of target cancer cells expressing specific membrane-bound surface antigens (Zahavi ...).
Here's how ADCC works:
- Antibody Binding: Antibodies (typically IgG class) bind to specific antigens on the surface of the target cell (e.g., a cancer cell or a virus-infected cell). The Fab regions of the antibody bind to the antigen.
- Effector Cell Recognition: Effector cells, such as Natural Killer (NK) cells, macrophages, neutrophils, and eosinophils, express Fc receptors (specifically, Fcγ receptors like CD16) on their surface. These receptors bind to the Fc region (the tail end) of the antibodies that are coating the target cell.
- Activation and Killing: The binding of multiple Fc receptors to antibodies on the target cell surface activates the effector cell. Activated effector cells then release cytotoxic molecules (like perforin and granzymes, similar to CTLs, especially by NK cells) or pro-inflammatory cytokines, leading to the lysis or apoptosis of the antibody-coated target cell.
ADCC is particularly relevant in defense against certain viruses, bacteria, and in mediating the effects of some therapeutic antibodies used to treat cancer or autoimmune diseases.
Comparing CTL-Mediated Killing and ADCC
Here's a simplified comparison of these two key mechanisms:
| Feature | CTL-Mediated Killing | Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) |
|---|---|---|
| Primary Effector Cell | Cytotoxic T Lymphocytes (CTLs) | NK cells, Macrophages, Eosinophils, Neutrophils |
| Target Recognition | TCR recognizes antigen presented by MHC Class I | Effector cell Fc receptor binds antibody on target |
| Requirement | MHC Class I on target cell | Antibody coating target cell |
| Specificity | Highly specific to antigen-MHC complex | Specificity determined by antibody |
| Mechanism | Perforin/Granzyme, FasL/Fas pathways | Perforin/Granzyme release, cytokine secretion |
| Targets | Intracellular pathogens, cancer cells | Antibody-coated targets (viruses, bacteria, tumors) |
These mechanisms are vital components of the adaptive and innate immune responses, providing robust defenses against cellular threats.
