Project acronym menTORingTregs
Project Unravelling paradoxes in regulatory T cell biology: the molecular basis for an mTOR-dependent oscillatory metabolic switch controlling immune tolerance and autoimmunity
Researcher (PI) Giuseppe Matarese
Host Institution (HI) CONSIGLIO NAZIONALE DELLE RICERCHE
Call Details Starting Grant (StG), LS6, ERC-2012-StG_20111109
Summary 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.
Summary
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.
Max ERC Funding
1 500 000 €
Duration
Start date: 2013-05-01, End date: 2018-04-30
Project acronym STEPS
Project Signalling compartmentalization and vesicle Trafficking at the Phagocytic Synapses
Researcher (PI) Antonella Viola
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PADOVA
Call Details Advanced Grant (AdG), LS6, ERC-2012-ADG_20120314
Summary A key feature of the immune response is its specificity and macrophages must be able to discriminate precisely between an infectious stimulus and a non-infectious one and tune their response in accordance with the molecular context in which the target particle is recognized. In recent years, scientists have proposed the concept of the phagocytic synapse, to stress the fact that a particle does not engage only one receptor on the cell surface; instead, an array of receptors interacts with a specific pathogen, either sequentially or simultaneously. Indeed, the tightly controlled and specific responses of macrophages require the establishing of checkpoints for signalling and the phagocytic synapse represent an exquisite site for cross-talk among several signalling pathways. Although we can describe detailed signalling pathways for most of the single receptors acting at the phagocytic synapse, we still do not know how these pathways are integrated during the various phases of macrophage responses. An integrated view of phagocytic synapse signalling would allow us to understand the contribution of each ligand-receptor pair to macrophage dysfunctions in pathology and to design novel immunotherapeutic strategies.
The aim of STePS is to provide a deeper understanding of the molecular interactions leading to the orchestration of phagocytic synapses for phagocytosis and activation, two events crucial for immune responses to pathogens as well as for inflammation. In particular, we will focus on three fundamental aspects that bring together the fields of immunology and cell biology: establishment of dynamic platforms for recognition and signalling at the plasma membrane; vesicle trafficking to the plasma membrane; signalling compartmentalization for specific cell functions. Importantly, these mechanisms will be analyzed in the context of physiological and pathological conditions, thus providing answers to both basic and translational biomedical research questions.
Summary
A key feature of the immune response is its specificity and macrophages must be able to discriminate precisely between an infectious stimulus and a non-infectious one and tune their response in accordance with the molecular context in which the target particle is recognized. In recent years, scientists have proposed the concept of the phagocytic synapse, to stress the fact that a particle does not engage only one receptor on the cell surface; instead, an array of receptors interacts with a specific pathogen, either sequentially or simultaneously. Indeed, the tightly controlled and specific responses of macrophages require the establishing of checkpoints for signalling and the phagocytic synapse represent an exquisite site for cross-talk among several signalling pathways. Although we can describe detailed signalling pathways for most of the single receptors acting at the phagocytic synapse, we still do not know how these pathways are integrated during the various phases of macrophage responses. An integrated view of phagocytic synapse signalling would allow us to understand the contribution of each ligand-receptor pair to macrophage dysfunctions in pathology and to design novel immunotherapeutic strategies.
The aim of STePS is to provide a deeper understanding of the molecular interactions leading to the orchestration of phagocytic synapses for phagocytosis and activation, two events crucial for immune responses to pathogens as well as for inflammation. In particular, we will focus on three fundamental aspects that bring together the fields of immunology and cell biology: establishment of dynamic platforms for recognition and signalling at the plasma membrane; vesicle trafficking to the plasma membrane; signalling compartmentalization for specific cell functions. Importantly, these mechanisms will be analyzed in the context of physiological and pathological conditions, thus providing answers to both basic and translational biomedical research questions.
Max ERC Funding
2 350 342 €
Duration
Start date: 2013-04-01, End date: 2019-03-31
