University of Dundee

EASTBIO: Defining the T cell receptor signalosome in intestinal intraepithelial lymphocytes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership http://www.eastscotbiodtp.ac.uk/how-apply-0. This opportunity is open to UK and EU nationals.

Applicants should apply by completing the EASTBIO application form (downloadable from the EASTBIO website) and e-mail to EASTBIOapplications@dundee.ac.uk. Candidates should also include their academic transcripts and ensure that they ask their referees to send completed references to EASTBIOapplications@dundee.ac.uk. Applicants may wish to explain their motivation for joining the EASTBIO training programme.

Intraepithelial lymphocytes (IEL) are the first immune cells that pathogens encounter in the gut. These T lymphocytes lie withinthe epithelial layer, and are central to controlling infection, stress or transformation of the gut epithelium. At the same time, deregulation of IEL responses can lead to inflammatory bowel diseases such as Coeliac and Crohn’s disease. Despite their importance, we have a poor understanding of how IEL sense and respond to stress and infection of the intestinal epithelia. Moreover, despite IEL expressing a variable, antigen-specific, T cell antigen receptor (TCR), it is unclear when the TCR is activated, and how it signals in these unconventional T cells.The aim of this project is to integrate experimental and computational approaches to gain a systems-level overview of TCR signalling in IEL. The student will use state-of-the-art phosphoproteomics, single cell phospho-and epigenetic-profiling through high-content cytometry, combined with RNA sequencing, to get a global overview of the dynamic changes that occur in IEL upon TCR triggering and without.We will map the signalling and transcriptional networks utilised by these specialised lymphocytes using innovative software such as Cytoscape, Bioconductor, R and gene set enrichment analyses. The student will also address the relevance of identified signalling and transcriptional pathways for IEL function in vivo by studying infection of genetically modified mice with oral pathogens.The goal is to understand the relevance of the TCR in IEL function in health and inflammatory diseases, and identify new drug targets that could be used to manipulate IEL.

References:

1.Ross, S.H., Rollings, C., Anderson, K.E., Hawkins, P.T., Stephens, L.R., and Cantrell, D.A. (2016). Phosphoproteomic Analyses of Interleukin 2 SignalingReveal Integrated JAK Kinase-Dependent and -Independent Networks in CD8+ T Cells. Immunity 45, 685–700.

2.Swamy, M., Beck-García, K, et al. (2016). A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation. Immunity 44, 1091–1101.

3.Swamy, M., Abeler-Dörner, L., Chettle, J., et al. (2015). Intestinal intraepithelial lymphocyte activation promotes innate antiviral resistance. Nat Comms 6, 7090.

Eligibility