| Project Detail |
Intestinal gut T cell memory in chronic inflammation
The immune system, and T cells in particular, play a central role in maintaining gut health, defending against infections, and ensuring tolerance to beneficial gut microbiota. Understanding the mechanisms and regulation of intestinal T cell memory can lead to significant advancements in therapeutic interventions for intestinal diseases. Funded by the European Research Council, the GuT Memory project aims to investigate the long-term memory characteristics of T cells specific to non-pathogenic gut bacteria. Using newly engineered tools, researchers will delineate how bacterial exposure sequences shape T cell function and will assess their physiological relevance. This innovative approach shall enhance mucosal vaccine design and the targeting of pathogenic T cells in chronic inflammation.
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 defence and tolerance, but it is unknown whether they form immunological memory characterised 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.
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.
Mutant strains of non-pathogenic gut bacteria engineered to transiently colonise 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. With this, I aim to (1) elucidate how the longevity of such responses is regulated by host survival niches versus microbiota-mediated attrition. Uncovering (2) how the sequence of bacterial exposures and their microbial context shape the functional repertoire of such Th cells will demonstrate the impact of lineage flexibility on their protective versus pathogenic potential. (3) Ultimately, successive transient colonisations 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. 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. |
