Histone deacetylase 6 at crossroads of infection and innnate immunity
Author
Moreno Gonzalo, OlgaAdvisor
Sánchez Madrid, FranciscoEntity
UAM. Departamento de Bioquímica; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)Date
2018-05-25Funded by
This work has been performed at the Prof. Francisco Sánchez-Madrid’s laboratory in the Hospital Universitario de la Princesa (HUP) and Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid. This study was funded by grants SAF2014-55579-R from the Spanish Ministry of Economy and Competitiveness, INDISNET-S2011/ BMD-2332 from the Comunidad de Madrid, CIBERCARDIOVASCULAR and grant PIE13/00041 from the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria del Instituto de Salud Carlos III with co-funding from the Fondo Europeo de Desarrollo Regional; FEDER), and ERC-2011-AdG 294340- GENTRIS and COST-Action BM1202 from the European Comission to Francisco Sánchez- Madrid. The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). Olga Moreno was supported by a PhD fellowship from the Spanish Ministry of Education (FPU Program, FPU12/00733). I thank Dr. M. Gómez for assitance with English editing and for critical reading of this PhD thesis.Subjects
Enfermedades bacterianas - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 25-05-2018Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
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 (IFNγ) 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
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