perforingranzymemediated

Perforin-granzyme–mediated cytotoxicity is a cellular mechanism by which cytotoxic lymphocytes eliminate stressed, infected, or malignant target cells. The principal effector cells are CD8+ T cells (cytotoxic T lymphocytes) and natural killer (NK) cells, which recognize targets through antigen-specific receptors or activating receptors, respectively. Upon engagement, these effector cells release lytic granules at the immunological synapse that forms between the effector cell and the target.

The core molecular actors are perforin and granzymes. Perforin is a pore-forming protein that inserts into the target cell membrane in a calcium-dependent fashion, creating transmembrane pores. Granzymes are serine proteases contained in the same granules; they enter the target cell through the perforin-created pores. Granzyme B is particularly important for initiating caspase-dependent apoptosis by activating effector caspases such as caspase-3, and it can also promote mitochondrial outer membrane permeabilization via Bid cleavage. Granzyme A induces a caspase-independent form of cell death with distinct substrates. Granzymes are delivered with other granule components that can modulate the local environment and enhance cytotoxic efficacy.

This mechanism operates rapidly, typically within minutes, and complements other cytotoxic pathways such as death receptor signaling. Regulation is strict, to prevent unintended tissue damage; proper trafficking of granules relies on vesicle-associated proteins and cytoskeletal machinery, including SNAREs and regulators like Rab27a and Munc13-4. Dysfunction in perforin-granzyme pathways can lead to immunological disorders, most notably familial hemophagocytic lymphohistiocytosis, highlighting the essential role of this system in immune surveillance and homeostasis.