We study development and dysregulation of the immune system using computational and single cell genomics.
Immune cells are remarkably diverse, dynamic and communicative in nature. Our research aims to understand how this essential heterogeneity is established and how it is modified in inflammatory disease. We use functional genomics approaches to digitise immune cell states and then work computationally to generate molecular and systems-level insight. We are currently pursuing projects in two main areas:
THE ROLE OF THYMIC EPITHELIAL CELLS IN CENTRAL TOLERANCE
The adaptive immune system employs stochastic somatic V(D)J recombination to generate a diverse T-cell receptor repertoire capable of recognising unknown foreign antigens. For this strategy to succeed, T-cells acquiring self-reactive receptors must be deleted or directed to a regulatory fate. T-cell selection is centrally guided by thymic epithelial cells (TEC) which challenge naïve T-cells with a near-complete molecular mirror of self-antigens. This unusual ability of TEC to promiscuously express virtually all protein coding genes is poorly understood but depends in part on the autoimmune regulator, Aire, a factor essential for the avoidance of autoimmunity. In collaborative work funded by a 5 year Wellcome Trust Strategic Award we are using single cell genomics approaches to study the mechanics of promiscuous gene expression in TEC.
THE CELLULAR AND MOLECULAR BASIS OF CHRONIC INFLAMMATION
Chronic conditions such as inflammatory bowel disease (IBD) and inflammatory arthritis involve context-specific changes in the abundance and phenotype of a variety of immune cell types. For instance, in IBDs such as Crohn's Disease and Ulcerative Colitis, intestinal macrophages can adopt a spectrum of pro- and anti-inflammatory states. In research with the Udalova and Powrie groups we are using single-cell transcriptomics to characterise these states in order to identify novel therapeutic targets. In parallel, we are working to deploy ultra-high-throughput droplet-based single-cell RNA-seq methods for immune-phenotyping. We will use this technology to directly assay the cells, pathways and genes responsible for sustaining specific inflammatory conditions.