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Unravelling paradoxes in regulatory T cell biology: the molecular basis for an mTOR-dependent oscillatory metabolic switch controlling immune tolerance and autoimmunity

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.

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
Dirección
Piazzale Aldo Moro 7
00185 Roma
Italia
Tipo de actividad
Research Organisations
Aportación de la UE
€ 1 500 000
Investigador principal
Giuseppe Matarese (Dr.)
Contacto administrativo
Mario De Felice (Prof.)

Beneficiarios (1)

CONSIGLIO NAZIONALE DELLE RICERCHE
Italia
Aportación de la UE
€ 1 500 000
Dirección
Piazzale Aldo Moro 7
00185 Roma
Tipo de actividad
Research Organisations
Investigador principal
Giuseppe Matarese (Dr.)
Contacto administrativo
Mario De Felice (Prof.)