Intraepithelial T lymphocytes (IELs) are at the forefront of mucosal immunity - the first immune cells that pathogens and symbionts encounter in the gut. IELs are central to the protection of the gut against infection and dietary stress, but dysregulated IELs responses are also associated with autoimmune inflammatory bowel diseases such as Coeliac and Crohn’s disease. Importantly, these unique T cells reside between nutrient-absorptive intestinal epithelial cells, close to the anaerobic microbes in the intestinal lumen. How IELs are able to respond to changes in intestinal epithelial cells and how they influence nutrition absorption and epithelial defence is currently unclear (1).

The aim of this project is to investigate how specific molecular regulators in IELs allows them to adapt to the intestinal microenvironment and mount appropriate responses to intestinal perturbations, including diet and microbial challenges. The discovery that PIM kinases uniquely regulate metabolic activation of IEL (2), and that T-cell receptor signalling in IEL is uniquely modified (3) , and that IEL have a unique metabolic signature (4), all suggest that changes in these molecular components are necessary for IELs to function. In this project, the student will learn to use state-of-the-art techniques including proteomics and phosphoproteomics, Ribo-Seq to rapidly identify changes in IEL, and in vivo models to address how perturbations in signalling pathways regulate intestinal homeostasis.

These studies will provide fundamental insights into how these unique immune cells communicate with epithelial cells to maintain intestinal homeostasis, findings that can be leveraged therapeutically to tune IEL activity in infectious, autoimmune and/or metabolic diseases.

1. Vandereyken M, James OJ, Swamy M. Mechanisms of activation of innate-like intraepithelial T lymphocytes. Mucosal Immunol. 2020 Sep;13(5):721–31.

2. James OJ, Vandereyken M, Marchingo JM, Singh F, Bray SE, Wilson J, et al. IL-15 and PIM kinases direct the metabolic programming of intestinal intraepithelial lymphocytes. Nat Commun. 2021 Jul 13;12(1):4290.

3. Chawla AS, Watt HJ, Schattgen SA, Skariah N, Saha I, Warrick K, et al. Conserved developmental rewiring of the TCR signalosome drives tolerance in innate-like lymphocytes. bioRxiv. 2025 Jan 1;2023.09.01.555859.

4. Brenes AJ, Vandereyken M, James OJ, Watt H, Hukelmann J, Spinelli L, et al. Tissue environment, not ontogeny, defines murine intestinal intraepithelial T lymphocytes. Rothlin CV, editor. eLife. 2021 Sep 2;10:e70055.