Objetivo Our group has been investigating how the nutrient/energy-sensing mammalian target of rapamycin (mTOR)-pathway affects the responsiveness of CD4+CD25+FoxP3+ regulatory T cells (Tregs). We have shown that Tregs have a high metabolic profile associated with the hyperactivation of the mTOR-pathway, which is responsible for the in vitro anergy of these cells. A transient mTOR inhibition with rapamycin, before T-cell-receptor (TCR)-stimulation, induced Tregs proliferation in the absence of exogenous interleukin-2 (IL-2). While a transient mTOR inhibition was necessary to allow Tregs to enter the cell cycle upon TCR-engagement, proliferating Tregs increased the levels of activation of mTOR to sustain their own expansion overtime. These data indicated that the metabolic state influences Tregs fate and the responsiveness to TCR stimulation in a dynamic/oscillatory fashion through the mTOR-pathway. The results also suggested a new mechanism of regulation between metabolism and immune tolerance in the Tregs in which mTOR could be activated under physiological conditions in response to changes of the energy status. In the current project, we intend to further dissect the relationship between mTOR oscillating activity and Tregs responsiveness. We aim to dissect the molecular and cellular events that govern the responsiveness of Tregs in vitro and in vivo, and address the associated apparent paradoxes: 1)Why Tregs have high proliferation in vivo but are hyporesponsive to TCR stimulation in vitro? 2)Why the current strategies to facilitate the in vitro expansion of hyporesponsive Tregs require high doses of IL-2 together with rapamycin, which is a strong inhibitor of cell growth and proliferation? The conclusion of the studies proposed in this application will unravel important questions on the biology of Tregs and will have significant implication for furthering the understanding of basic mechanisms governing immune tolerance and autoimmunity. Ámbito científico natural sciencesbiological sciencescell biology Programa(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Tema(s) ERC-SG-LS6 - ERC Starting Grant - Immunity and infection Convocatoria de propuestas ERC-2012-StG_20111109 Consulte otros proyectos de esta convocatoria Régimen de financiación ERC-SG - ERC Starting Grant Institución de acogida CONSIGLIO NAZIONALE DELLE RICERCHE Aportación de la UE € 1 500 000,00 Dirección PIAZZALE ALDO MORO 7 00185 Roma Italia Ver en el mapa Región Centro (IT) Lazio Roma Tipo de actividad Research Organisations Investigador principal Giuseppe Matarese (Dr.) Contacto administrativo Mario De Felice (Prof.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos Beneficiarios (1) Ordenar alfabéticamente Ordenar por aportación de la UE Ampliar todo Contraer todo CONSIGLIO NAZIONALE DELLE RICERCHE Italia Aportación de la UE € 1 500 000,00 Dirección PIAZZALE ALDO MORO 7 00185 Roma Ver en el mapa Región Centro (IT) Lazio Roma Tipo de actividad Research Organisations Investigador principal Giuseppe Matarese (Dr.) Contacto administrativo Mario De Felice (Prof.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos