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Induction of T cell tolerance #RACE1

Kennedy Institute of Rheumatology

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Prof M Dustin , Dr C Hilkens No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

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


1. Heissmeyer V, Macian F, Im SH, Varma R, Feske S, Venuprasad K, Gu H, Liu YC, Dustin ML, Rao A. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol. 2004;5(3):255-65.
2. Valvo S, Mayya V, Seraia E, Afrose J, Novak-Kotzer H, Ebner D, Dustin ML. Comprehensive Analysis of Immunological Synapse Phenotypes Using Supported Lipid Bilayers. Methods Mol Biol. 2017;1584:423-41.
3. Anderson AE, Swan DJ, Wong OY, Buck M, Eltherington O, Harry RA, Patterson AM, Pratt AG, Reynolds G, Doran JP, Kirby JA, Isaacs JD, Hilkens CM. Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4(+) T cells partly via transforming growth factor-beta1. Clin Exp Immunol. 2017;187(1):113-23. Epub 2016/11/03. doi: 10.1111/cei.12870. PubMed PMID: 27667787; PMCID: PMC5167049.
4. Bell GM, Anderson AE, Diboll J, Reece R, Eltherington O, Harry RA, Fouweather T, MacDonald C, Chadwick T, McColl E, Dunn J, Dickinson AM, Hilkens CM, Isaacs JD. Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis. Ann Rheum Dis. 2017;76(1):227-34.
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