What Is Cell Mediated Cytotoxicity and How Does It Work?

Cell-mediated cytotoxicity is a surveillance process where immune cells directly find and eliminate infected or cancerous cells. This defense mechanism relies on specialized immune cells that can distinguish between healthy and compromised cells. This continuous activity removes harmful cells before they can cause widespread disease, forming a primary defense against internal threats.

Key Immune Cells Driving Cytotoxicity

Two principal types of immune cells carry out cell-mediated cytotoxicity: Cytotoxic T Lymphocytes (CTLs) and Natural Killer (NK) cells. Although they both destroy harmful cells, their origins and methods of target recognition differ, allowing them to function as complementary partners in immunity.

CTLs, also known as CD8+ T cells, are part of the adaptive immune system and are trained to recognize specific threats. These cells are activated when they encounter an antigen, which is a molecular signature from a pathogen or a mutated protein from a cancer cell. Healthy cells present their own protein fragments on Major Histocompatibility Complex (MHC) class I molecules, which CTLs ignore. When a cell is infected, it presents foreign fragments on these MHC molecules, flagging the cell for destruction.

NK cells are part of the innate immune system and do not require prior activation by a specific antigen. These cells identify targets by looking for cells that have stopped displaying MHC class I molecules on their surface, a tactic used by some viruses and cancers to evade CTLs. This “missing-self” recognition, along with detecting stress-induced proteins on a cell’s surface, triggers the NK cell’s cytotoxic functions.

The Process of Cell Elimination

Once a CTL or NK cell identifies a target, it initiates the elimination process. The primary method for both cell types is the granule exocytosis pathway. This involves releasing substances from lytic granules directly at the point of contact with the target cell.

Inside these granules are two main protein types: perforin and granzymes. Upon release, perforin creates pores or channels in the target cell’s outer membrane. These pores disrupt the cell membrane and serve as entry points for granzymes to enter the target cell’s cytoplasm.

Once inside, granzymes cleave various proteins, initiating a cascade that leads to programmed cell death, or apoptosis. This process dismantles the cell from the inside out, breaking down its DNA and structural components. Apoptosis is a controlled form of cell death that prevents the release of infectious agents or harmful substances that could cause inflammation.

A second mechanism involves a direct interaction between proteins on the immune and target cell surfaces. Activated CTLs and NK cells can express a protein called Fas ligand (FasL). If the target cell expresses a corresponding receptor called Fas, the binding of FasL to Fas triggers a signaling cascade inside the target cell that also culminates in apoptosis.

Guarding Health: Cytotoxicity in Action

Cell-mediated cytotoxicity eliminates virus-infected cells and those that have become cancerous. When a virus invades, it replicates inside the host cell, hiding it from immune components circulating outside. The direct destruction of the infected cell by a CTL or NK cell is necessary to halt viral production and prevent the infection from spreading.

This surveillance mechanism also prevents the development of cancer. Normal cells can mutate and become cancerous, but these transformed cells often display abnormal proteins or lose the “self” markers that cytotoxic cells monitor. CTLs and NK cells recognize these changes and eliminate the cells before they can form a tumor, a process known as immune surveillance.

The importance of this system is highlighted in individuals with genetic deficiencies affecting cytotoxic cell function. These individuals are highly susceptible to severe viral infections and certain types of cancer.

Therapeutic Innovations Leveraging Cytotoxicity

The understanding of cell-mediated cytotoxicity has led to new medical treatments, particularly in cancer immunotherapy. These therapies enhance the body’s natural cell-killing abilities to better target and destroy tumors. A prominent example is CAR T-cell therapy, which modifies a patient’s own CTLs to improve their cancer-fighting capabilities.

In CAR T-cell therapy, T cells are extracted from a patient’s blood and genetically engineered to express Chimeric Antigen Receptors (CARs). These synthetic receptors recognize specific antigens on cancer cells, allowing the modified T cells to attack tumors independent of MHC-based recognition. The engineered cells are then infused back into the patient to create a targeted anti-tumor response.

Researchers are also developing therapies using NK cells. These treatments often use cells from healthy donors, which can be prepared as an “off-the-shelf” therapy, reducing time and cost compared to personalized CAR T-cell treatments. These NK cells can also be engineered with CARs to enhance their tumor-targeting ability.

Beyond direct cell therapies, knowledge of cytotoxicity informs modern vaccine development. Vaccines can be designed to stimulate a strong CTL response, which is useful for protecting against intracellular pathogens like viruses or for therapeutic vaccines that train the immune system to attack existing cancer cells.