Key Points
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Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells kill virus-infected and transformed cells through both the death-receptor and granule exocytosis pathways. The perforin-dependent granule exocytosis mechanism is crucial for protecting the host against many viral infections, and in mice this pathway is involved in immune surveillance of certain spontaneous cancers, especially B-cell lymphomas.
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In both humans and rodents, perforin is crucial for the function of the granule exocytosis pathway, as it is required for the trafficking of granzymes to their pro-apoptotic substrates in the target cell. Deficiency in perforin results in severe immune dysregulation. By contrast, deficiencies in single granzymes result in milder immunodeficiency phenotypes.
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Perforin is encoded by a single gene, and although its primary sequence has some similarity to portions of the complement components that make up the membrane-attack complex, it is otherwise unique. The toxicity of perforin in various expression systems has made it difficult to study its structure and function. However, suitable and informative expression modalities have recently been developed.
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In humans, congenital perforin deficiency accounts for 30–60% of known cases of the severe immunodeficiency disorder familial haemophagocytic lymphohistiocytosis (FHL). Infants typically present with marked enlargement of the liver and lymphoid organs, anaemia and sometimes neurological deficits, frequently following an otherwise innocuous viral infection.
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Some of the missense mutations that are associated with FHL have proved invaluable in defining the normal function of certain perforin residues and domains. As a result, we now understand the basis for calcium binding to the C2 domain of perforin, which is necessary for perforin to bind irreversibly to the target-cell plasma membrane.
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The Ala91Val mutation in perforin is a common isoform in some human populations and had previously been considered an innocent polymorphism. Recent evidence from several groups indicates that the Ala91Val mutation might result in loss of perforin function, raising the issue of why this allele has persisted in the human population.
Abstract
The granule exocytosis pathway of cytotoxic lymphocytes is crucial for immune surveillance and homeostasis. The trafficking of granule components, including the membrane-disruptive protein perforin, to the immunological synapse leads to the delivery of granule proteases (granzymes) into the target cell and its destruction through apoptosis. Several independent molecular abnormalities associated with defects of either granule trafficking or perforin function can cause cytotoxic lymphocyte dysfunction. In humans, inherited perforin mutations result in severe immune dysregulation that manifests as familial haemophagocytic lymphohistiocytosis. This Review describes recent progress in defining the structure, function, biochemistry and cell biology of perforin.
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Acknowledgements
M.J.S. and J.A.T. are supported by senior fellowships and a program grant from the National Health and Medical Research Council of Australia. J.A.T. and I.V. are supported by a program grant from the Juvenile Diabetes Research Foundation. We also thank the many members of the Cancer Immunology Program and our collaborators for contributions over the years to many of the findings referred to in this Review.
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Glossary
- Haemophagocytosis
-
The phagocytosis of erythrocytes that results from excessive activation of macrophages. This is usually a consequence of uncontrolled activation and proliferation of T cells.
- Thrombocytopaenia
-
A reduced number of circulating platelets, owing to either the failure of production from bone-marrow megakaryocytes or increased clearance from the blood, predominantly in the spleen.
- SET complex
-
A 270–420 kDa multiprotein complex that is associated with the endoplasmic reticulum. Pro-apoptotic granzyme A cleaves components of the SET complex, such as the nuclear assembly protein SET, the DNA-bending protein HMG2 and the base-excision repair pathway apurinic endonuclease APE1.
- Ectromelia
-
A natural poxvirus pathogen of mice that is similar to variola virus (smallpox) in humans and vaccinia virus (cowpox) in cows. Cytotoxic T lymphocyes and natural killer cells from mice that are deficient in granzyme A and B or perforin are incapable of controlling primary infection with ectromelia virus.
- Nonsense mutation
-
A mutation that results in the introduction of a stop codon to cause the premature termination of the protein.
- Missense mutation
-
A mutation that results in the substitution of an amino acid in a protein.
- SNARE
-
(Soluble-N-ethylmaleimide-sensitive-factor accessory-protein receptor). A complex formed between the vesicle and the target membrane, with which it is destined to fuse. t-(target membrane) SNAREs on target-membranes, and v-(vesicle-associated) SNAREs on transport vesicles cooperate with other proteins to allow docking and fusion of membranes.
- Heterozygosity
-
The proportion of individuals in a population that carry two different alleles at a locus.
- Hodgkin's lymphoma
-
A B-cell lymphoma that is characterized by the presence of Reed–Sternberg cells; it is observed in the lymph nodes, spleen, liver and bone marrow. It is more commonly diagnosed in younger people (median age 33 years).
- Non-Hodgkin's lymphoma
-
A lymphocytic B- or T-cell lymphoma. This lymphoma is more common among older people (median age 65 years).
- BCR–ABL
-
A tyrosine kinase oncogene. The Abelson leukaemia-virus protein (ABL) is fused with the breakpoint-cluster region (BCR) in the Philadelphia-chromosome translocation found in chronic myeloid leukaemia.
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Voskoboinik, I., Smyth, M. & Trapani, J. Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol 6, 940–952 (2006). https://doi.org/10.1038/nri1983
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DOI: https://doi.org/10.1038/nri1983
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