Deciphering Antigen-Specific Circuits Orchestrating Tolerance.

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).

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.
2. With this, we will explore the different instructions pTreg communicates to APC subsets (Aim 2).
3. 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.