What Are Granzymes and How Do They Protect the Body?

Granzymes are a family of enzymes called serine proteases used by the immune system to eliminate threats. These proteins are synthesized and stored within specialized immune cells and are released to target cells that are virally infected or have become cancerous. Once released, granzymes can trigger a process of programmed cell death, effectively instructing a harmful cell to self-destruct.

The Immune Cells That Wield Granzymes

The primary immune cells responsible for deploying granzymes are Cytotoxic T Lymphocytes (CTLs) and Natural Killer (NK) cells. Both cell types survey the body for threats. CTLs are highly specific, recognizing fragments of foreign proteins on the surface of infected or cancerous cells, signaling an attack. NK cells are part of the innate immune system and can identify and eliminate target cells without prior sensitization.

These defender cells store granzymes in specialized compartments called cytotoxic granules. Upon identifying a target, these granules are directed toward the harmful cell for release. While there are several types of granzymes, such as Granzyme A, B, H, K, and M, Granzyme B is one of the most extensively studied for its ability to induce cell death. Granzyme A has different primary targets and can initiate cell death through a separate pathway.

Although CTLs and NK cells are the main producers, other immune cells like dendritic cells, B cells, and mast cells can also express granzymes. Even some non-immune cells, such as keratinocytes in the skin, produce these enzymes. This wider distribution suggests granzymes have functions beyond targeted cell killing, including immune regulation and tissue maintenance.

How Granzymes Induce Target Cell Death

The process of granzyme-induced cell death begins with the formation of an immunological synapse, a tight connection between the immune cell and its target. Once this connection is established, the immune cell releases the contents of its cytotoxic granules into this space. For granzymes to be effective, they must gain entry into the target cell’s interior with help from a partner protein called perforin.

Perforin is a pore-forming protein that creates channels in the membrane of the target cell. These pores act as gateways, allowing granzymes to move from the outside of the cell into the cytoplasm. This delivery mechanism is precise, ensuring the granzymes are unleashed only inside the intended target and minimizing damage to healthy neighboring cells.

Once inside, granzymes set off a cascade of events leading to apoptosis, or programmed cell death. Granzyme B, for example, functions by cleaving and activating a group of proteins called caspases. These activated caspases then systematically dismantle the cell from within by breaking down structural components and chopping up the DNA. This controlled demolition prevents the release of harmful substances that could trigger inflammation.

Granzymes as Key Defenders Against Disease

The primary role of granzymes is to defend against internal threats like viral infections. By using granzymes to eliminate infected cells, the immune system can control viral loads and prevent widespread infection before a virus can spread.

Granzymes are also part of the body’s surveillance against cancer. Immune cells use them to destroy mutated cells before they can form tumors, a process known as immune surveillance. This action reduces the risk of tumor development and spread.

Beyond viruses and cancer, granzymes can also target intracellular bacteria. Granzymes A and B have been shown to induce lethal damage in bacteria by disrupting their metabolic processes. This demonstrates their broad-spectrum capability against pathogens that hide within cells.

The Double-Edged Sword: Granzymes in Sickness and Treatment

While granzymes are defenders, their unregulated activity can contribute to disease. In chronic inflammatory conditions and autoimmune diseases, excessive or misplaced granzyme activity can lead to tissue damage. When granzymes are released into the extracellular space, they can degrade components of the extracellular matrix, the structural scaffolding that holds tissues together, which can exacerbate inflammation.

This dual nature makes granzymes relevant in medicine. In cancer immunotherapy, treatments are designed to boost the ability of a patient’s own T cells to find and kill tumor cells. The effectiveness of these therapies relies on the granzyme-mediated killing mechanism. Understanding how to enhance the delivery and activity of granzymes is a major focus of cancer research.

Conversely, in conditions driven by excessive inflammation, inhibiting granzyme activity is being explored as a therapeutic strategy. Developing drugs that can specifically block extracellular granzymes could help reduce tissue damage in autoimmune disorders without compromising the immune system’s ability to fight off infections.