Investigating the role of environmental sensing in frontline memory T cell responses

Enduring immunological memory is dependent on T cells that reside in frontline tissues. The formation and persistence of these tissue-resident memory T cells (TRM) are controlled by tissue-specific environmental signals, but how communication with local environments shapes TRM biology is unclear, and studying these mechanisms in human TRM remains a significant challenge. The aryl hydrocarbon receptor (AHR) is a key environmental sensor and targetable ligand-activated transcription factor with known involvement in the core TRM transcriptional program. I will investigate how AHR signalling impacts TRM biology in mice and humans at a cellular and molecular level, and develop platforms to make human TRM study significantly easier and more accessible. First, through in silico deconstruction of mouse and human transcriptomic datasets, I will home in on AHR pathway associations in TRM populations. Next, I will study the impact of AHR on TRM generation, maintenance, function, and plasticity in intestinal and liver tissues following murine enteric infection. Finally, 3D gut culture and organ-on-chip models will be utilised to study molecular interactions in human TRM in vitro. This research will advance our understanding of TRM persistence, and offer the platform to better study human TRM, accelerating knowledge of disease processes and supporting targeted vaccine development.