The intestinal immune system must continuously balance protective immunity to pathogens with tolerance to self antigens, diet, and harmless commensal microbes. Failure to maintain this balance underlies chronic inflammatory diseases, food allergy, and autoimmunity, yet the regulatory principles that maintain intestinal immune homeostasis remain poorly understood. Central to this process are Foxp3-expressing regulatory T (Treg) cells, whose sustained activity is essential to suppress lethal autoimmunity and allergic inflammation. Recent work has revealed that intestinal Treg cells comprise at least two distinct subsets defined by developmental origin and transcriptional programming. How these specialized Treg cells acquire their identity and how Treg cells exert their suppressive effects within complex tissue environments remain fundamental open questions.
The proposal addresses these questions by establishing a conceptual and technological framework to “deconstruct” intestinal immune tolerance. The overarching objective is to define the molecular and cellular networks that maintain intestinal immune homeostasis, with a focus on transcriptional control, cell–cell interactions, and developmental timing. By employing acute and reversible chemical-genetic perturbations, the project aims to identify the direct gene regulatory functions of Treg cell-specific transcription factors and the subset-specific activities of intestinal Treg cell populations.
The expected impact of this work is twofold. Conceptually, it will provide fundamentally new insights into how immune tolerance is established, maintained, and disrupted in a vital barrier tissue. Methodologically, it will deliver broadly applicable genetic strategies to interrogate gene regulation and immune cell function in complex organs with unprecedented precision. Together, these advances have the potential to reshape our understanding of immune regulation and inform future approaches to treat inflammatory and autoimmune diseases of the intestine.
