SubsidieMeestersDeciphering Antigen-Specific Circuits Orchestrating Tolerance.
This project aims to uncover the cellular interactions governing peripheral regulatory T cell responses to gut microbes, enhancing understanding of tolerance mechanisms for treating inflammation-related conditions.
Projectdetails
Introduction
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 for conditions like allergies and inflammatory bowel disease.
Role of Antigen-Presenting Cells
Antigen-presenting cells (APCs) play a pivotal role in governing tolerance:
- They induce pTreg.
- They support their terminal differentiation and maintenance.
- They 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.
Recent Discoveries
We and two other groups recently identified ROR(gamma)t+ APCs as the exclusive initiators of the pTreg response to gut microbes. This discovery, along with our newly developed methodological approaches, now provides a unique opportunity to delve into the cellular interactions utilized by pTreg.
Research Aims
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).
Conclusion
By unraveling antigen-specific circuits, we strive for a novel understanding of tolerance mechanisms.
Financiële details & Tijdlijn
Financiële details
| Subsidiebedrag | € 2.175.000 |
| Totale projectbegroting | € 2.175.000 |
Tijdlijn
| Startdatum | 1-8-2024 |
| Einddatum | 31-7-2029 |
| Subsidiejaar | 2024 |
Partners & Locaties
Projectpartners
- WEIZMANN INSTITUTE OF SCIENCEpenvoerder
Land(en)
Vergelijkbare projecten binnen European Research Council
| Project | Regeling | Bedrag | Jaar | Actie |
|---|---|---|---|---|
Deconstructing Intestinal Immune ToleranceThis project aims to dissect the intestinal immune regulatory network using chemical genetic protein degradation to understand the role of Foxp3+ Treg cells in maintaining immune tolerance. | ERC Starting... | € 1.500.000 | 2024 | Details |
T cell regulation by fed state bacterial metabolitesThis project aims to identify immunoregulatory bacterial molecules produced in response to food intake, enhancing understanding of gut microbiome tolerance mechanisms and their impact on intestinal health. | ERC Starting... | € 1.499.548 | 2024 | Details |
The role of GPCRs and homing molecules in the control and regionalization of mucosal immunity.This project aims to investigate the role of GPCRs, particularly GPR35, in immune regionalization of mucosal tissues to enhance understanding and treatment of gut and airway diseases. | ERC Starting... | € 1.500.000 | 2024 | Details |
Microbiota-T cell interactions - antigen-specificity and regulation in health and diseaseThis project aims to identify and characterize microbe-specific T cells to understand their role in chronic inflammatory diseases and aging, paving the way for targeted therapies. | ERC Starting... | € 1.500.000 | 2022 | Details |
Dissecting the context-specificity of genetic immune regulation in plasmacytoid dendritic cellsThe project aims to uncover the genetic regulation and functional diversity of plasmacytoid dendritic cells to explain variability in antiviral responses and autoimmune diseases across diverse populations. | ERC Starting... | € 1.499.235 | 2023 | Details |
Deconstructing Intestinal Immune Tolerance
This project aims to dissect the intestinal immune regulatory network using chemical genetic protein degradation to understand the role of Foxp3+ Treg cells in maintaining immune tolerance.
T cell regulation by fed state bacterial metabolites
This project aims to identify immunoregulatory bacterial molecules produced in response to food intake, enhancing understanding of gut microbiome tolerance mechanisms and their impact on intestinal health.
The role of GPCRs and homing molecules in the control and regionalization of mucosal immunity.
This project aims to investigate the role of GPCRs, particularly GPR35, in immune regionalization of mucosal tissues to enhance understanding and treatment of gut and airway diseases.
Microbiota-T cell interactions - antigen-specificity and regulation in health and disease
This project aims to identify and characterize microbe-specific T cells to understand their role in chronic inflammatory diseases and aging, paving the way for targeted therapies.
Dissecting the context-specificity of genetic immune regulation in plasmacytoid dendritic cells
The project aims to uncover the genetic regulation and functional diversity of plasmacytoid dendritic cells to explain variability in antiviral responses and autoimmune diseases across diverse populations.