title: 15 kDa granulysin causes differentiation of monocytes to dendritic cells but lacks cytotoxic activity.
abstract: Granulysin is expressed as two isoforms by human cytotoxic cells: a single mRNA gives rise to 15 kDa granulysin, a portion of which is cleaved to a 9 kDa protein. Studies with recombinant 9 kDa granulysin have demonstrated its cytolytic and proinflammatory properties, but much less is known about the biologic function of the 15 kDa isoform. In this study, we show that the subcellular localization and functions of 9 and 15 kDa granulysin are largely distinct. Nine kilodalton granulysin is confined to cytolytic granules that are directionally released following target cell recognition. In contrast, 15 kDa granulysin is located in distinct granules that lack perforin and granzyme B and that are released by activated cytolytic cells. Although recombinant 9 kDa granulysin is cytolytic against a variety of tumors and microbes, recombinant 15 kDa granulysin is not. The 15 kDa isoform is a potent inducer of monocytic differentiation to dendritic cells, but the 9 kDa isoform is not. In vivo, mice expressing granulysin show markedly improved antitumor responses, with increased numbers of activated dendritic cells and cytokine-producing T cells. Thus, the distinct functions of granulysin isoforms have major implications for diagnosis and potential new therapies for human disease.
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Clayberger
authors.forename: Michael W
authors.initials: MW
authors.lastname: Finn
authors.forename: Tianhong
authors.initials: T
authors.lastname: Wang
authors.forename: Reena
authors.initials: R
authors.lastname: Saini
authors.forename: Christine
authors.initials: C
authors.lastname: Wilson
authors.forename: Valarie A
authors.initials: VA
authors.lastname: Barr
authors.forename: Marianna
authors.initials: M
authors.lastname: Sabatino
authors.forename: Luciano
authors.initials: L
authors.lastname: Castiello
authors.forename: David
authors.initials: D
authors.lastname: Stroncek
authors.forename: Alan M
authors.initials: AM
authors.lastname: Krensky
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009000:Monocytes / Q000166:cytology* / Q000276:immunology; D009374:Neoplasms, Experimental / Q000276:immunology*; D020033:Protein Isoforms
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; C075005:GNLY protein, human; D020033:Protein Isoforms