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T cell receptor binding affinity and immune activation in chronic inflammatory disease. (#202006)

About This PhD Project

Project Description

Activation of immune cells, and in particular the activation of T cells by antigens, has been shown to play a key role in the onset of a range of chronic inflammatory disorders, including inflammatory bowel disease and rheumatoid arthritis. T cell activation is triggered by signalling via a complex immune synapse that forms between T cells and antigen presenting cells. The intensity and characteristics of this activation depend on a host of factors, including the presence of other signalling proteins (called costimulators) within the immune synapse, and the strength of the bond (binding affinity) between the presented antigen and the T cell receptor. This project will study the role of T cell receptor binding affinity on activation, in order to map the cellular and downstream genomic differences between high and low affinity activation, and to establish whether differences in response to low or high affinity T cell activation can explain why certain individuals are at higher risk of chronic inflammatory disease.

This is a joint experimental and computational project, and the student will learn to use both advanced experimental immunology techniques and a range of computational biology and statistical genetics tools.

The wet-lab component will involve developing experimental systems to invoke high and low affinity T cell receptor activation, through synthesis of modified low- and high-affinity monoclonal antibodies and through engineering of cells to respond to high or low affinity natural antigens. The student will use cellular immunology techniques to measure the impact of these different forms of activation on cellular phenotypes in cells from patients and from healthy volunteers. They will use advance imaging techniques to investigate differences in the structure of the immune synapse formed during low and high affinity activation, and to investigate how binding affinity interacts with the presence of other costimulatory molecules.

The computational component of this project will involve generating and analysing functional genomic data, including RNA-seq to measure gene expression and ATAC-seq to measure epigenetic regulation, and using bioinformatics pipelines to establish genome-wide differences in downstream signalling pathways between high and low affinity activation. The student will also use statistical genetics techniques to establish how affinity-dependent regulatory pathways confer genetic risk for different chronic inflammatory diseases, by integrating their data with the results of genome-wide association studies.

Training Opportunities

Detailed training and experience of molecular and cellular immunology techniques, including cell culture, flow cytometry, protein synthesis, transfection and cellular imaging. This will include training in cutting edge imaging techniques via the Kennedy Institute’s Cellular Dynamics Platform, run by Michael Dustin.

Training in computational data analysis and programming, including training and hands-on experience of the statistical programming language R, and in high-performance computing. Training in computational skills is a priority for the Kennedy Institute, and the student will have access to expertise in cutting edge computational software and hardware, as well as access to our bespoke computational cluster KGen.

Training in computational biology, including in analysis of RNA-seq and other functional genomics data. This will include both formal training and peer mentorship through the Kennedy Institute’s Computational Biology Forum.

Training in statistical genetics, including the analysis of GWAS and eQTL data, and techniques for integrating GWAS data with functional genomics results. Training will be carried out within the Jostins group, and through hands-on experience in international genetics consortia.

Key Publications

Dafni et al (2018) Genomic profiling of T cell activation reveals dependency of memory T cells on CD28 costimulation.

Dustin and Baldari (2017) The Immune Synapse: Past, Present, and Future. Methods Mol Biol. 1584:1-5.

De Lange et al (2017) Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet. 49(2): 256–261.

Huang et al (2017) Fine-mapping inflammatory bowel disease loci to single variant resolution. Nature. 547(7662): 173–178.

Schubert DA, Gordo S, Sabatino JJ, Jr., Vardhana S, Gagnon E, Sethi DK, Seth NP, Choudhuri K, Reijonen H, Nepom GT, Evavold BD, Dustin ML, Wucherpfennig KW. Self-reactive human CD4 T cell clones form unusual immunological synapses. J Exp Med. 2012;209(2):335-52. Epub 2012/02/09. doi: 10.1084/jem.20111485. PubMed PMID: 22312112

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