Engineered symbionts elucidate gut T cell memory and its (dys)regulation

Introduction

A detailed understanding of intestinal T cell memory is crucial for novel treatments against inflammatory bowel disease but also for efficient vaccine design. Th cells induced by the gut microbiota are important for pathogen defense and tolerance, but it is unknown whether they form immunological memory characterized by long-term, antigen-independent maintenance. This has been due to the technical inability of disconnecting T cell induction from bacterial persistence in the gut.

Project Overview

The GuT Memory project will yield unique insights into microbiota-directed Th cell memory and its (dys)regulation through uncoupling Th cell induction from luminal persistence of the microbe.

Methodology

1. Experimental Design
   Mutant strains of non-pathogenic gut bacteria engineered to transiently colonize germ-free mice will be combined with state-of-the-art adoptive transfer experiments to trace antigen-specific Th cells into the memory phase after their inducing bacterium has been cleared from the gut.

2. Research Aims
   With this, I aim to:

   • (1) Elucidate how the longevity of such responses is regulated by host survival niches versus microbiota-mediated attrition.
   • (2) Uncover how the sequence of bacterial exposures and their microbial context shape the functional repertoire of such Th cells, demonstrating the impact of lineage flexibility on their protective versus pathogenic potential.
   • (3) Ultimately, successive transient colonizations will provide a novel approach to dissect the physiological relevance of microbiota-specific memory Th cells for the luminal microbe, host protection, and epithelial function.

Impact

These findings will aid mucosal vaccine design and indicate novel approaches to target pathogenic Th cells in chronic inflammatory disorders. The ground-breaking nature of this proposal lies in the innovation of being able to uncouple microbiota-mediated T cell induction from luminal antigen persistence to understand how T cell maintenance is fine-tuned to promote host–microbial mutualism while avoiding aberrant inflammation.