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Functional significance of the perforin/granzyme cell death pathway

Functional significance of the perforin/granzyme cell death pathway Key Points Perforin/granzyme-induced apoptosis is the main pathway used by cytotoxic lymphocytes to kill virus-infected and transformed cells. The main function of the FAS–FAS ligand (FASL) pathway is to maintain homeostasis of the lymphoid compartment. Studies in gene-disrupted mice indicate that perforin is vital for cytotoxic effector function. Perforin-deficient mice are abnormally susceptible to many viruses and other intracellular pathogens, they fail to reject certain types of allograft and they are highly susceptible to spontaneous B-cell lymphomas as they age. In certain situations, perforin deficiency is associated with reduced immunopathology. For example, non-obese diabetic (NOD) mice that lack perforin develop islet inflammation, but are protected from autoimmune destruction of their pancreatic β-cells and have a reduced incidence of diabetes compared with wild-type NOD mice. The molecular functions of perforin are not well understood. Perforin has an indispensable role in delivering granzyme B and other granule toxins to the cytosol of target cells. However, the hypothesis that perforin pores allow the passive diffusion of granzymes into cells is not consistent with recent experimental data, and this model is probably an over-simplification. Recently, a subset of patients with the rare immunodeficiency disease familial haemophagocytic lymphohistiocytosis (FHL) were found to have missense and/or nonsense mutations in both of their perforin alleles. The catalogue of deduced perforin mutations should enable researchers to define in more detail the basis of the normal molecular functions of perforin. Granzymes trigger several apoptotic pathways in target cells; some of them are dependent on caspases, but others can kill cells when caspases are inhibited, for example by viral proteins that block intrinsic apoptotic pathways. Deficiency of an individual granzyme might be associated with focal immune deficits — for example, the marked susceptibility of granzyme-A- or -B-deficient mice and, particularly, granzyme A and B double-deficient mice to the poxvirus ectromelia. The same animals do not have increased susceptibility to related poxviruses. Perforin protects mice against the development of spontaneous B-cell lymphoma and carcinogen-induced sarcoma. It remains to be determined whether surveillance against other cancers, particularly epithelial malignancies, is affected in perforin-deficient mice. In addition to determining whether a virus is cleared or persists, the effector pathway that is selected by killer lymphocytes (perforin/granzyme, FASL or interferon-γ) can influence immunopathology, often in an organ-specific manner. Many mechanisms of immune escape that operate at the level of reduced antigen presentation have been described for virus-infected and malignant cells. It is now becoming increasingly clear that alternative mechanisms can operate at the level of inhibiting effector-cell function. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Reviews Immunology Springer Journals

Functional significance of the perforin/granzyme cell death pathway

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References (132)

Publisher
Springer Journals
Copyright
Copyright © Nature Publishing Group 2002
Subject
Biomedicine; Biomedicine, general; Immunology
ISSN
1474-1733
eISSN
1474-1741
DOI
10.1038/nri911
Publisher site
See Article on Publisher Site

Abstract

Key Points Perforin/granzyme-induced apoptosis is the main pathway used by cytotoxic lymphocytes to kill virus-infected and transformed cells. The main function of the FAS–FAS ligand (FASL) pathway is to maintain homeostasis of the lymphoid compartment. Studies in gene-disrupted mice indicate that perforin is vital for cytotoxic effector function. Perforin-deficient mice are abnormally susceptible to many viruses and other intracellular pathogens, they fail to reject certain types of allograft and they are highly susceptible to spontaneous B-cell lymphomas as they age. In certain situations, perforin deficiency is associated with reduced immunopathology. For example, non-obese diabetic (NOD) mice that lack perforin develop islet inflammation, but are protected from autoimmune destruction of their pancreatic β-cells and have a reduced incidence of diabetes compared with wild-type NOD mice. The molecular functions of perforin are not well understood. Perforin has an indispensable role in delivering granzyme B and other granule toxins to the cytosol of target cells. However, the hypothesis that perforin pores allow the passive diffusion of granzymes into cells is not consistent with recent experimental data, and this model is probably an over-simplification. Recently, a subset of patients with the rare immunodeficiency disease familial haemophagocytic lymphohistiocytosis (FHL) were found to have missense and/or nonsense mutations in both of their perforin alleles. The catalogue of deduced perforin mutations should enable researchers to define in more detail the basis of the normal molecular functions of perforin. Granzymes trigger several apoptotic pathways in target cells; some of them are dependent on caspases, but others can kill cells when caspases are inhibited, for example by viral proteins that block intrinsic apoptotic pathways. Deficiency of an individual granzyme might be associated with focal immune deficits — for example, the marked susceptibility of granzyme-A- or -B-deficient mice and, particularly, granzyme A and B double-deficient mice to the poxvirus ectromelia. The same animals do not have increased susceptibility to related poxviruses. Perforin protects mice against the development of spontaneous B-cell lymphoma and carcinogen-induced sarcoma. It remains to be determined whether surveillance against other cancers, particularly epithelial malignancies, is affected in perforin-deficient mice. In addition to determining whether a virus is cleared or persists, the effector pathway that is selected by killer lymphocytes (perforin/granzyme, FASL or interferon-γ) can influence immunopathology, often in an organ-specific manner. Many mechanisms of immune escape that operate at the level of reduced antigen presentation have been described for virus-infected and malignant cells. It is now becoming increasingly clear that alternative mechanisms can operate at the level of inhibiting effector-cell function.

Journal

Nature Reviews Immunology – Springer Journals

Published: Oct 1, 2002

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