Computational Immunomics Group – Dr Steve Sansom, Kennedy Institute

We are using single cell approaches to investigate thymic mechanisms of central tolerance and to study immune cell responses in inflammatory disease.

1.  The role of thymic epithelial cells (TEC) in central tolerance

The adaptive immune system has the ability to recognise virtually any foreign (non-self) antigen due to the generation of a random T-cell receptor repertoire via VD(J) recombination. However, in order to avoid autoimmunity, T-cells bearing self-reactive receptors must first be systematically identified and rendered non-reactive to self – a process essential for central tolerance. This process takes place in the thymus, where TEC challenge developing T-cells with a “molecular mirror” of self-antigens. In a recent analysis of population and single cell genomics data we found TEC to promiscuously express ninety percent of the protein coding genome in a process that is apparently stochastic at the single cell level1. This work continues as part of a Wellcome Trust Strategic Award - “The Homunculus in our Thymus” – which has been described separately by Professor Georg Holländer.

2.  Immune cell responses in inflammatory disease

Inflammatory disorders such as inflammatory bowel disease (IBD) and rheumatoid arthritis involve changes in the abundances and phenotypes of diverse immune cell types. We are looking to use single-cell approaches to understand these responses, initially focusing on cells of the innate immune system such as macrophages. In IBDs, such as Crohn’s disease and ulcerative colitis, infiltrating pro-inflammatory macrophages rapidly become abundant in the intestine where they are understood to drive inflammation. We are hence using a single-cell RNA-seq approach to study macrophage phenotypes in a mouse model of IBD (collaboration with Alastair Corbin, Professor Irina Udalova and Professor Fiona Powrie). Looking ahead we plan to use single cell (e.g. RNA-seq, ATAC-seq, CyTOF) and population genomics approaches to more broadly study the immune system in inflammatory conditions. For this work we would like to implement higher throughput, lower cost approaches such as Drop-seq.

Collaboration with Fluidigm
We are involved – as part of the Wellcome Trust Strategic Award – in collaborations with Fluidigm on a combination of single cell protein detection and transcriptomics.

References
Sansom SN, Shikama N, Zhanybekova S, Nusspaumer G, Macaulay IC, Deadman ME, Heger A, Ponting CP, Holländer GA. Population and single cell genomics reveal the Aire-dependency,relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia.Genome Res. 2014 Dec;24(12):1918-31