Serglycin determines secretory granule repertoire and regulates natural killer cell and cytotoxic T lymphocyte cytotoxicity
| Autor: | Sarah Ellis, Ricky W. Johnstone, Kevin Y. T. Thia, Daniel M. Andrews, Ilia Voskoboinik, Amelia J. Brennan, Vivien R. Sutton, Gunnar Pejler, Joseph A. Trapani, Jill Danne, Misty R. Jenkins |
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| Rok vydání: | 2016 |
| Předmět: |
Male
Pore Forming Cytotoxic Proteins 0301 basic medicine Vesicular Transport Proteins Mice Transgenic Cell Separation CD8-Positive T-Lymphocytes Biology Biochemistry Granzymes Natural killer cell Mice 03 medical and health sciences Interleukin 21 Microscopy Electron Transmission medicine Animals Serglycin Mast Cells Molecular Biology Cells Cultured Crosses Genetic CD11b Antigen Lymphokine-activated killer cell Secretory Vesicles Degranulation Cell Biology Flow Cytometry Tumor Necrosis Factor Receptor Superfamily Member 7 Cell biology Killer Cells Natural Mice Inbred C57BL Granzyme B 030104 developmental biology medicine.anatomical_structure Granzyme Proteolysis biology.protein Granzyme A Female Proteoglycans T-Lymphocytes Cytotoxic |
| Zdroj: | FEBS Journal. 283:947-961 |
| ISSN: | 1742-464X |
| DOI: | 10.1111/febs.13649 |
| Popis: | The anionic proteoglycan serglycin is a major constituent of secretory granules in cytotoxic T lymphocyte (CTL)/natural killer (NK) cells, and is proposed to promote the safe storage of the mostly cationic granule toxins, granzymes and perforin. Despite the extensive defects of mast cell function reported in serglycin gene-disrupted mice, no comprehensive study of physiologically relevant CTL/NK cell populations has been reported. We show that the cytotoxicity of serglycin-deficient CTL and NK cells is severely compromised but can be partly compensated in both cell types when they become activated. Reduced intracellular granzyme B levels were noted, particularly in CD27(+) CD11b(+) mature NK cells, whereas serglycin(-/-) TCR-transgenic (OTI) CD8 T cells also had reduced perforin stores. Culture supernatants from serglycin(-/-) OTI T cells and interleukin-2-activated NK contained increased granzyme B, linking reduced storage with heightened export. By contrast, granzyme A was not significantly reduced in cells lacking serglycin, indicating differentially regulated trafficking and/or storage for the two granzymes. A quantitative analysis of different granule classes by transmission electronmicroscopy showed a selective loss of dense-core granules in serglycin(-/-) CD8(+) CTLs, although other granule types were maintained quantitatively. The findings of the present study show that serglycin plays a critical role in the maturation of dense-core cytotoxic granules in cytotoxic lymphocytes and the trafficking and storage of perforin and granzyme B, whereas granzyme A is unaffected. The skewed retention of cytotoxic effector molecules markedly reduces CTL/NK cell cytotoxicity, although this is partly compensated for as a result of activating the cells by physiological means. |
| Databáze: | OpenAIRE |
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