Perforin

Perforin is a pore-forming protein expressed mainly by cytotoxic T lymphocytes and natural killer cells. It is a key effector molecule of cellular immunity, enabling cytotoxic lymphocytes to eliminate infected or transformed cells by delivering granzymes into their cytosol.

Perforin belongs to the membrane attack complex/perforin (MACPF) superfamily. It is stored in cytotoxic granules together with granzymes and is released at the immunological synapse upon target recognition. In the extracellular milieu with sufficient calcium, perforin monomers polymerize and insert into the target cell plasma membrane, forming transmembrane pores. These pores allow granzymes to access cytosolic substrates and activate apoptotic pathways.

The PRF1 gene encodes perforin in humans. Proper perforin function requires correct processing, granule targeting, and calcium-dependent pore formation. Genetic defects in PRF1 reduce cytotoxic cell activity and can lead to familial hemophagocytic lymphohistiocytosis type 2 (FHL2), a life-threatening hyperinflammatory syndrome characterized by ineffective cytotoxicity and widespread immune activation.

In addition to its role in normal immune defense, perforin dysfunction has been studied in the context of infectious diseases and cancer immunology, where cytotoxic lymphocyte activity is important for controlling pathogens and tumor cells. Understanding perforin biology informs approaches to diagnose immune disorders and to design therapies that modulate cytotoxic responses.