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Despite the extensive defects of mast cell function reported in serglycin gene\u2010disrupted mice, no comprehensive study of physiologically relevant <jats:styled-content style=\"fixed-case\">CTL<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> cell populations has been reported. We show that the cytotoxicity of serglycin\u2010deficient <jats:styled-content style=\"fixed-case\">CTL<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> 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<jats:sup>+<\/jats:sup>CD11b<jats:sup>+<\/jats:sup> mature <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> cells, whereas serglycin<jats:sup>\u2212\/\u2212<\/jats:sup> <jats:styled-content style=\"fixed-case\">TCR<\/jats:styled-content>\u2010transgenic (<jats:styled-content style=\"fixed-case\">OTI<\/jats:styled-content>) CD8 T cells also had reduced perforin stores. Culture supernatants from serglycin<jats:sup>\u2212\/\u2212<\/jats:sup> <jats:styled-content style=\"fixed-case\">OTI<\/jats:styled-content> T cells and interleukin\u20102\u2010activated <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> 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\u2010core granules in serglycin<jats:sup>\u2212\/\u2212<\/jats:sup> CD8<jats:sup>+<\/jats:sup> <jats:styled-content style=\"fixed-case\">CTL<\/jats:styled-content>s, 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\u2010core 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 <jats:styled-content style=\"fixed-case\">CTL<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> cell cytotoxicity, although this is partly compensated for as a result of activating the cells by physiological means.<\/jats:p>","DOI":"10.1111\/febs.13649","type":"journal-article","created":{"date-parts":[[2016,1,12]],"date-time":"2016-01-12T14:27:44Z","timestamp":1452608864000},"page":"947-961","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Serglycin determines secretory granule repertoire and regulates natural killer cell and cytotoxic T lymphocyte cytotoxicity"],"prefix":"10.1111","volume":"283","author":[{"given":"Vivien R.","family":"Sutton","sequence":"first","affiliation":[{"name":"Cancer Cell Death\/Killer Cell Biology Laboratories Peter MacCallum Cancer Centre East Melbourne Victoria 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