Dissecting the code for regulatory T cell entry into the tissues and differentiation into tissue-resident cells

Foxp3+ regulatory T cells (Tregs) are highly potent immunosuppressive cells. Most of our understanding of Tregs is based on the population present in lymphoid tissues, however to harness their anti-inflammatory power in the clinic we need to understand the tissue-resident population. Converting generic Tregs into expanded proto-tissue Tregs, capable of entering inflamed tissues, adapting to local conditions, and driving an anti-inflammatory pro-rejuvenation process would transform cell therapy. However to be able to encode a tissue-resident function into Tregs, we first need to decode the cellular induction signals that allow a Treg to become a tissue Treg, and decode the molecular processes of Treg tissue entry and reprogramming into the residential phenotype.This project seeks to dissect Treg tissue-residency at an unprecedented scale. The applicant’s team has developed and validated cutting-edge technology, “FlowCodes”, to enable massively-parallel functional testing of the tissue Treg repertoire and genetic control. The project will test the cellular behaviour of ~500 tissue Treg TCRs and ~500 gut Treg TCRs through retrogenic TCR analysis, across multiple organs, in health and disease, identifying the site of Treg induction and disease-responsiveness for each. The project will further test ~400 potential genetic cofactors (migration genes, transcription factors, metabolic adaptors), for contribution to tissue residency and potential to aid anti-inflammatory responses. Finally, the project will provide a proof-of-concept for re-encoding the identified residency features, and systematically test combinations of decoded TCR and genetic factors for the ability to augment tissue-residency and disease suppression in Tregs. The project therefore not only unravels the biological rules for Treg residency, it provides a pathway back to Treg cell therapy engineering.