Identification of molecular pathways that control regulatory T cell function in the intestine

PROJECT OVERVIEW

The gastrointestinal (GI) tract is home to trillions of commensal bacteria that play an important role in nutrition, immune system development and host defence. In inflammatory bowel disease (IBD), a chronic debilitating disease of the gastrointestinal tract, there is a breakdown in the healthy dialogue between our body and our microbial residents resulting in chronic immune attack in the bowel. Work in the Powrie lab has identified the regulatory T cell (Treg) axis as crucial in control of intestinal inflammation through the production of key anti-inflammatory cytokines IL-10 and TGF-beta. Recent work indicates that peripherally induced Treg cells reactive with commensal bacteria play an important role in intestinal homeostasis.

This project will build on recent studies in the lab tracking Treg responses to intestinal bacteria to identify key cellular interactions and molecular pathways that control Treg cell activation and effector function particularly in y tissue niches within the intestine.

The project will involve the use of novel TCR transgenic mouse strains, intravital microscopy, spatial transcriptomics and bioinformatic approaches to visualise and map Treg responses in vivo. Our recent work has identified some key interaction partners including ILC2 and macrophage subpopulations. Functional characterisation of these pathways will include the use of genetically modified mouse strains with cell type specific deletions of candidate pathways.

This project will provide novel insights into how Treg cells adapt in specific intestinal niches and how a breakdown in this dialogue can disrupt Treg function leading to intestinal inflammation. This information will inform therapeutic strategies to harness Tregs in autoimmune and inflammatory diseases. As the lab has a strong translational focus, pathways identified can be assessed in IBD patients.

KEYWORDS

Regulatory T cell, Inflammation, Immune regulation, microbiome, inflammatory bowel disease.

TRAINING OPPORTUNITIES

Training in conceptual and experimental aspects of immunology and microbiome.
Cutting edge technologies including live cell imaging, T cell biology, genetically modified mice, spatial transcriptomics and bioinformatics.

KEY PUBLICATIONS

1. Uhlig HH, Powrie F. 2018 Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease. Annu Rev Immunol.;36:755-781.
2. Whibley N, Tucci A, Powrie F. 2019 Regulatory T cell adaptation in the intestine and skin. Nat Immunol. 2019 (4):386-396.
3. Friedrich M, Pohin M, Jackson MA, Korsunsky I, Bullers SJ, Rue-Albrecht K, Christoforidou Z, Sathananthan D, Thomas T, Ravindran R, Tandon R, Peres RS, Sharpe H, Wei K, Watts GFM, Mann EH, Geremia A, Attar M; Oxford IBD Cohort Investigators; Roche Fibroblast Network Consortium, McCuaig S, Thomas L, Collantes E, Uhlig HH, Sansom SN, Easton A, Raychaudhuri S, Travis SP, Powrie FM. IL-1-driven stromal-neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies. Nat Med. 2021 Nov;27(11):1970-1981.
4. Miragaia RJ, Gomes T, Chomka A, Jardine L, Riedel A, Hegazy AN, Whibley N, Tucci A, Chen X, Lindeman I, Emerton G, Krausgruber T, Shields J, Haniffa M, Powrie F, Teichmann SA. 2019 Single-Cell Transcriptomics of Regulatory T Cells Reveals Trajectories of Tissue Adaptation. Immunity 50(2):493-504.e7.
5. Gu, Y.*, Bartolomé-Casado, R.*, Xu, C., Janney, A., Heuberger, C., Pearson, C., Teichmann, S., Thornton, E.E.*, Powrie, F.*, 2022. Intestinal lamina propria supports acquired eTreg suppressor function. https://doi.org/10.1101/2022.08.26.505428

KEY THEMES

Immunity and microbiome, tissue biology, inflammation.