Induction of T cell tolerance #RACE1

Supervisory team
Hub 1: Oxford – Prof. Michael Dustin (Lead Supervisor)
Hub 2: Newcastle – Catharien Hilkens

Project Description: Dendritic cells (DC) play a central role in inducing T-cell tolerance to self-antigens, thereby avoiding destructive autoimmune responses. This project aims to define the key DC-derived signals involved in T-cell tolerance. Interactions between T cells and candidate tolerogenic surface molecules on DC, defined by surface proteomics and transcriptomics, will be investigated by high-resolution imaging. Dendritic cells (DC) are specialized for activation of naïve T cells and regulatory T cells. Under steady state conditions this activation leads to tolerance to presented antigens. In vitro production of tolerogenic DC (TolDC) has been accomplished, but the key chemical signals and physical characteristics leading to tolerance in T cells are poorly understood. Out hypothesis is that surface proteins of different types of TolDC can be identified using a bottom up approach with supported lipid bilayers and purified proteins guided by molecular analysis of tolDC phenotypes. Using multiple omics modalities the student will identify candidate tolerogenic macromolecules presented on different types of TolDC, determine the in vitro response profiles of T cells induced by types of TolDC presenting self-antigens to naïve or memory T cells and test tolerogenic surfaces and use computational approaches to identify minimum set of macromolecules that trigger tolerance in naïve T cells or favour activation of Treg. The work will take place at the University of Oxford and Newcastle University.

Skills developed: cellular immunology; super resolution microscopy, quantitative cytometry, proteomics, protein biology and lipid bilayer biology, transcriptomics; biophysics