Procesos inducidos en la célula dentrítica tras la formación de la sinapsis inmunológica y sus efectos sobre la activación temprana del linfocito T
Director (es)Rodríguez Fernández, José Luis
EntidadUAM. Departamento de Biología Molecular; CSIC. Centro de Investigaciones Biológicas (CIB)
Fecha de edición2013-07-17
MateriasInmunología - Tesis doctorales; Biología celular - tesis doctorales; Biología molecular - Tesis doctorales; Biología y Biomedicina / Biología
NotaTesis doctoral inédita, leída en Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 17/07/2013.
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Dendritic cells (DCs) are the most important antigen presenting cells and they are able to initiate the immunological response through the activation of naïve T cells. The activation of these T cells takes place in the lymph nodes and requires tight contact with antigen presenting DCs. In vivo and in vitro studies indicate that during these interactions a specialized cell-cell junction called immunological synapse (IS) forms at the region of contact between DCs and T cells. The IS includes membrane and cytoplasmic components at the T cell and DC side, regions called IS (T cell) and IS (DC), respectively. Most studies on the IS have focused on the structure and functions of the IS (T cell) and there is sparse information available on the IS (DC) and its role in T cell activation. In this work we show that antigen-specific IS formation between DCs and CD4 T cells leads to a rapid upsurge of mitochondrial ROS in DCs in vitro and in vivo. As indicated before for T cells, in the DCs forming IS the mitochondria also redistribute to the vicinity of the IS region, suggesting that clustering of mitochondria in this region and the production of ROS are coordinated. In addition, we show that the increase in ROS production after IS formation triggers mitochondrial depolarization in DCs. We also demonstrate that upon IS formation in DCs autophagy and mitophagy, two well-established mechanisms of quality control involved in the removal of damage proteins and organelles like mitochondria, are induced. Indeed, the presence of autophagosomes and signaling molecules controlling autophagy and mitophagy at the vicinity of the IS (DC) indicates that these processes are active at this region. Our data also confirm that IS-induced autophagy in DCs is not caused by ROS, as shown in other settings, because it is not affected by general inhibition of ROS production by treating the DCs with anti-oxidant agents or the selective inhibition of mitochondrial ROS by treatment with MitoQ. All these results were confirmed using Atg5-/- DCs. We have observed an increase in mitochondrial number in these cells, suggesting defect in mitophagy. Atg5-/- DCs also show an increase in ROS production, whose generation is blocked by treatment with MitoQ. Most importantly, IS formation is not able to up-regulate ROS production in these cells, indicating that autophagy/mitophagy in DCs is necessary to allow IS-dependent control of ROS up-regulation. Finally we investigated the role of these mitochondrial ROS generated in DCs, and we show that up-regulation of ROS in DCs upon IS formation controls early signaling events during T cell activation. All these data together uncover a novel mechanism whereby the IS (DC) may modulate T cells activation and proliferation.
Google Scholar:Gómez Cabañas, Laura
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