title: Protein kinase C delta localizes to secretory lysosomes in CD8+ CTL and directly mediates TCR signals leading to granule exocytosis-mediated cytotoxicity.
abstract: Lytic granule exocytosis is the major effector function used by CD8(+) CTL in response to intracellular pathogens and tumors. Despite recent progress in the field, two important aspects of this cytotoxic mechanism remain poorly understood. First, TCR-signaling pathway(s) that selectively induces granule exocytosis in CTL has not been defined to date. Second, it is unclear how Ag receptor-induced signals are converted into mobilization of lytic granules. We recently demonstrated that protein kinase C delta (PKC delta) selectively regulates TCR-induced lytic granule polarization in mouse CD8(+) CTL. To better understand how PKC delta facilitates granule movement, here we studied dynamics of intracellular localization of PKC delta in living CD8(+) CTL. Strikingly, we found that PKC delta localizes to the secretory lysosomes and polarizes toward immunological synapse during the process of target cell killing. Also, biochemical and structure-function studies demonstrated that upon TCR ligation, PKC delta becomes rapidly phosphorylated on the activation loop and regulates granule exocytosis in a kinase-dependent manner. Altogether, our current studies provide new insights concerning the regulation of TCR-induced lytic granule exocytosis by revealing novel intracellular localization of PKC delta, providing the first example of colocalization of a kinase with secretory lysosomes in CD8(+) CTL and demonstrating that PKC delta directly transduces TCR signals leading to polarized granule secretion.
authors.affiliation: Center for Cancer and Immunology, Children's National Medical Center, Children's Research Institute, Washington, DC 20010, USA.
authors.forename: Jennifer S Y
authors.initials: JS
authors.lastname: Ma
authors.forename: Tarik F
authors.initials: TF
authors.lastname: Haydar
authors.forename: Sasa
authors.initials: S
authors.lastname: Radoja
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D054992:Immunological Synapses / Q000235:genetics; D007939:Leukemia L1210; D008247:Lysosomes / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051745:Protein Kinase C-delta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D011948:Receptors, Antigen, T-Cell; C497259:Prkcd protein, mouse; D051745:Protein Kinase C-delta