title: HDAC6 regulates the dynamics of lytic granules in cytotoxic T lymphocytes.
abstract: HDAC6 is a tubulin deacetylase involved in many cellular functions related to cytoskeleton dynamics, including cell migration and autophagy. In addition, HDAC6 affects antigen-dependent CD4(+)T cell activation. In this study, we show that HDAC6 contributes to the cytotoxic function of CD8(+)T cells. Immunization studies revealed defective cytotoxic activity in vivo in the absence of HDAC6. Adoptive transfer of wild-type or Hdac6(-/-)CD8(+)T cells to Rag1(-/-)mice demonstrated specific impairment in CD8(+)T cell responses against vaccinia infection. Mechanistically, HDAC6-deficient cytotoxic T lymphocytes (CTLs) showed defective in vitro cytolytic activity related to altered dynamics of lytic granules, inhibited kinesin-1-dynactin-mediated terminal transport of lytic granules to the immune synapse and deficient exocytosis, but not to target cell recognition, T cell receptor (TCR) activation or interferon (IFN)γ production. Our results establish HDAC6 as an effector of the immune cytotoxic response that acts by affecting the dynamics, transport and secretion of lytic granules by CTLs.
authors: Servicio de Inmunología, Hospital Universitario de la Princesa, UAM, IIS-IP. Madrid, 28006 Spain.|Laboratory of Intercellular communication, Fundación CNIC, Madrid, 28029 Spain.
authors: Norman
authors: N
authors: Núñez-Andrade
authors: Immunobiology of inflammation, Fundación CNIC, Madrid, 28029 Spain.
authors: Salvador
authors: S
authors: Iborra
authors: Microscopy and Dynamic Imaging Unit, Fundación CNIC, Madrid, 28029 Spain.|Spettroscopia biomedica in fluorescenza dinamica, Center of Experimental Imaging, Ospedale San Raffaele, Milan, 20132, Italy.
authors: Antonio
authors: A
authors: Trullo
authors: Servicio de Inmunología, Hospital Universitario de la Princesa, UAM, IIS-IP. Madrid, 28006 Spain.|Laboratory of Intercellular communication, Fundación CNIC, Madrid, 28029 Spain.
authors: Olga
authors: O
authors: Moreno-Gonzalo
authors: Proteomic Unit. Fundación CNIC, Madrid, 28029 Spain.
authors: Enrique
authors: E
authors: Calvo
authors: Dept. Biochemistry and Molecular and Cell Biology, Universidad de Zaragoza, 500009, Spain.
authors: Elena
authors: E
authors: Catalán
authors: Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM Unité Mixte de Recherche 1163, Paris France.
authors: Gaël
authors: G
authors: Menasche
authors: Immunobiology of inflammation, Fundación CNIC, Madrid, 28029 Spain.
authors: David
authors: D
authors: Sancho
authors: Proteomic Unit. Fundación CNIC, Madrid, 28029 Spain.
authors: Jesús
authors: J
authors: Vázquez
authors: Departments of Pharmacology and Cancer Biology Duke University, Medical Center, Durham, North Carolina 27710, U.S.
authors: Tso-Pang
authors: TP
authors: Yao
authors: Servicio de Inmunología, Hospital Universitario de la Princesa, UAM, IIS-IP. Madrid, 28006 Spain.|Laboratory of Intercellular communication, Fundación CNIC, Madrid, 28029 Spain.
authors: Noa Beatriz
authors: NB
authors: Martín-Cófreces
authors: Servicio de Inmunología, Hospital Universitario de la Princesa, UAM, IIS-IP. Madrid, 28006 Spain.|Laboratory of Intercellular communication, Fundación CNIC, Madrid, 28029 Spain.
authors: Francisco
authors: F
authors: Sánchez-Madrid
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology*; D000072159:Dynactin Complex / Q000037:antagonists & inhibitors; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D016547:Kinesins / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014615:Vaccinia / Q000276:immunology*
chemical_list: D000072159:Dynactin Complex; D007371:Interferon-gamma; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C475469:Kif5b protein, mouse; D016547:Kinesins
keywords: Histone deacetylase 6; Kinesin 1; Lytic granule