Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules

• Published in: Nature reviews. Immunology Vol. 10; no. 8; pp. 568 - 579
• Main Authors: de Saint Basile, Geneviève, Ménasché, Gaël, Fischer, Alain
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2010; Nature Publishing Group
• Subjects: 631/250/2152/1566/1572; 631/250/516; 631/80/313/1481; Animals; Antigen-presenting cells; Antigens; AP-3 protein; Apoptosis; Biological Transport; Biomedical and Life Sciences; Biomedicine; Biosynthesis; Cell death; Cellular Biology; Cytoplasmic Granules - metabolism; Cytotoxicity; Cytotoxicity, Immunologic - physiology; Endopeptidases; Exocytosis; Exocytosis - immunology; Homeostasis; Human health and pathology; Humans; Immune response; Immune response (cell-mediated); Immunological synapses; Immunological Synapses - physiology; Immunology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Life Sciences; Ligands; Lymphocytes; Lymphocytes T; Molecular modelling; Mutants; Mutation; Natural killer cells; Neurotransmitter Agents - metabolism; Perforin; Physiological aspects; Proteins; review-article; Secretory Vesicles - metabolism; Serine proteinase; Syntaxin; T cells; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Transformed cells; Tumor necrosis factor-TNF; France; Paris France
• ISSN: 1474-1733; 1474-1741; 1474-1741
• DOI: 10.1038/nri2803

Key Points
Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are armed to kill virus-infected or transformed cells through the polarized secretion of cytotoxic granules that contain perforin and granzymes. Perforin is crucial for the access of granzymes to their pro-apoptotic substrates in the target cells.
Inherited deficiencies of the granule-dependent cytotoxic pathway in humans result in a severe immunopathological condition known as haemophagocytic lymphohistiocytosis (HLH). HLH is generally triggered by an infection and is associated with an overactive T cell-mediated immune response, probably resulting from the failure of activated CTLs and NK cells to clear antigen-presenting cells and thus to terminate the immune response.
Characterization of the molecular causes leading to HLH in humans and mutant mice has substantially contributed to our understanding of the key steps required for the maturation and exocytosis of cytotoxic granules during target cell killing. In addition to defects in perforin, which account for the prototypical form of HLH, defects in lysosomal trafficking regulator (LYST) or adaptor protein 3 (AP3) provide evidence for the role of these proteins in cytotoxic granule biogenesis.
The coordinated delivery of cytotoxic granule contents to the immunological synapse depends on additional effector proteins, which cause HLH when defective. They are involved in the docking (RAB27a), priming (MUNC13-4) and fusion (syntaxin 11 and MUNC18-2) of the cytotoxic granules that polarize at the CTL–target cell interface.
The structure of the immunological synapse is strikingly similar to that of the neurological synapse. In both cases, the delivery of mediators to the intercellular cleft must be tightly regulated in a spatial and temporal manner. Several of the effector proteins that mediate vesicle exocytosis at both synapses belong to the same families of proteins.
A comparison of the proteins and mechanisms involved may provide clues to uncover additional effectors that regulate the cytotoxic function of lymphocytes.
A complex and highly regulated pathway ensures that the delivery of cytotoxic cargo of cytotoxic lymphocytes is appropriately aimed and timed. As reviewed here, the study of patients and mutant mice with cytotoxicity defects has revealed many of the molecules involved in this targeted exocytosis of cytotoxic granules.
Cytotoxic T cells and natural killer cells are crucial for immune surveillance against virus-infected cells and tumour cells. Molecular studies of individuals with inherited defects that impair lymphocyte cytotoxic function have also highlighted the importance of cytotoxicity in the regulation and termination of immune responses. As discussed in this Review, characterization of these defects has contributed to our understanding of the key steps that are required for the maturation of cytotoxic granules and the secretion of their contents at the immunological synapse during target cell killing. This has revealed a marked similarity between cytotoxic granule exocytosis at the immunological synapse and synaptic vesicle exocytosis at the neurological synapse. We explore the possibility that comparison of these two kinetically and spatially regulated secretory pathways will provide clues to uncover additional effectors that regulate the cytotoxic function of lymphocytes.