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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

Objectif

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.

Appel à propositions

ERC-2012-StG_20111109
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Régime de financement

ERC-SG - ERC Starting Grant

Institution d’accueil

CONSIGLIO NAZIONALE DELLE RICERCHE
Adresse
Piazzale Aldo Moro 7
00185 Roma
Italie

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Type d’activité
Research Organisations
Chercheur principal
Giuseppe Matarese (Dr.)
Contact administratif
Mario De Felice (Prof.)
Contribution de l’UE
€ 1 500 000

Bénéficiaires (1)

CONSIGLIO NAZIONALE DELLE RICERCHE
Italie
Contribution de l’UE
€ 1 500 000
Adresse
Piazzale Aldo Moro 7
00185 Roma

Voir sur la carte

Type d’activité
Research Organisations
Chercheur principal
Giuseppe Matarese (Dr.)
Contact administratif
Mario De Felice (Prof.)