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Deciphering Antigen-Specific Circuits Orchestrating Tolerance.

Project description

Peripheral regulatory T cells for medical innovation

Peripheral regulatory T cell (pTreg) responses play a crucial role in inhibiting inflammation to harmless external antigens. Studying these responses holds promise for developing treatments for allergies and inflammatory bowel disease. Understanding antigen-presenting cells (APCs) is vital, as they are key to governing tolerance and inducing pTreg. In this context, the ERC-funded pTreg Circuit project has identified the exclusive initiator of the pTreg response to gut microbes. It aims to further investigate this initiator to discover additional exclusive initiators. Moreover, it plans to develop a toolbox for detecting and profiling specific antigen presenters using single-cell sequencing.

Objective

Peripheral regulatory T cell (pTreg) responses are critical in inhibiting inflammation to external harmless antigens. Studying their regulation and function is crucial for developing treatments to conditions like allergies and inflammatory bowel disease. Antigen-presenting cells (APCs) play a pivotal role in governing tolerance: they induce pTreg, support their terminal differentiation and maintenance and are also modulated by pTreg cells in their antigen-specific tasks. However, unclear findings regarding which cells initiate the pTreg response, coupled with the perception that APC subsets may play a redundant role, have made it challenging to fully understand and explore these critical cellular interactions. Therefore, a major gap existed in our ability to decipher the information exchange within the antigen-specific circuit orchestrating tolerance.

We and two other groups recently identified ROR(gamma)t+ APCs as the exclusive initiators of the pTreg response to gut microbes. This discovery, and our newly developed methodological approaches, now provide a unique opportunity to delve into the cellular interactions utilized by pTreg. Building on our previous findings and experimental strategies, we will adopt a reductionist approach to uncover which APCs, beyond RORγt+ cells, shape and maintain the pTreg response (Aim 1). We will combine the chimeric mice method with mouse genetics to devise a new approach that will allow us to conduct functional studies of the pTreg response without inducing inflammation and subsequent indirect effects. With this, we will explore the different instructions pTreg communicates to APC subsets (Aim 2). Lastly, drawing on my expertise in technology development, we will create a toolbox that allows, for the first time, detection and profiling of specific antigen presenters using single-cell sequencing (Aim 3).

By unraveling antigen-specific circuits, we strive for a novel understanding of tolerance mechanisms.

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HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

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(opens in new window) ERC-2024-STG

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Host institution

WEIZMANN INSTITUTE OF SCIENCE
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 2 175 000,00
Address
HERZL STREET 234
7610001 Rehovot
Israel

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Activity type
Higher or Secondary Education Establishments
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Total cost

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€ 2 175 000,00

Beneficiaries (1)

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