Perforin-1 and Granzyme B (PRF1/GZMB)

The perforin/granzyme-mediated cytolysis pathway is the primary mechanism employed by effector T cells, specifically CD8+ cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, to eliminate virus-infected or malignant cells (Voskoboinik et al., 2006, Nature Reviews Immunology). This process involves the regulated exocytosis of cytotoxic granules containing the pore-forming protein perforin-1 (PRF1) and a family of serine proteases known as granzymes, with granzyme B (GZMB) being the most potent pro-apoptotic member (UniProt P14222; UniProt P10144). Upon release into the immunological synapse, perforin-1 oligomerizes to form transmembrane pores in the target cell membrane, facilitating the entry of granzymes into the target cell cytoplasm. Once internalized, granzyme B triggers apoptosis by cleaving and activating caspases and the pro-apoptotic Bcl-2 family member Bid (StatPearls, "Physiology, Cytotoxic T Cells"). This pathway is a critical effector arm of the adaptive immune system and is the functional target of various immunotherapies, including immune checkpoint inhibitors like pembrolizumab and CAR-T cell therapies like tisagenlecleucel, which seek to restore or enhance the cytolytic capacity of T cells against tumors (PubMed, PMID: 28407992). Deficiencies in this pathway, particularly mutations in the PRF1 gene, lead to severe immune dysregulation such as familial hemophagocytic lymphohistiocytosis (NIH, Genetics Home Reference).

Other names

Perforin/Granzyme pathwayCytotoxic T-lymphocyte-mediated cytolysisPore-forming proteinGranzyme BPerforin-1GZMBPRF1

Induction of target cell apoptosis via pore formation and subsequent proteolytic activation of the caspase cascade.