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Regulatory T-cells (Tregs) play a key role in maintaining immune system homeostasis by regulating autoreactive effector T cells (Teffs). This homeostatic balance is lost in many autoimmune and inflammatory diseases, including type 1 diabetes (T1D), during which Teffs attack pancreatic beta cells, leading to insulin deficiency and organ damage. Interleukin-2 (IL-2) is the predominant cytokine responsible for regulating Treg levels and function. Early stage clinical trials have shown that low doses of IL-2 stimulate Treg expansion and function without stimulating Teffs. Tregs are highly heterogeneous in phenotype and function. Different Treg subsets have distinct roles in immune homeostasis and can be differentially targeted in the treatment of autoimmune disease. A deeper understanding of Treg functional heterogeneity will lead to the discovery and development of novel Treg-orientated therapies. To date, all studies and trials of IL-2 therapy have been limited to blood. However, the circulating T-cell populations only represent a shadow of what is happening in tissue.  

Through collaboration with the NHS and paediatric gastroenterologists, our group is able to routinely obtain gut biopsies from children with autoimmune and autoinflammatory diseases, along with healthy controls. Technologies for profiling single cell transcriptomes and proteomes are rapidly evolving, enabling the study of rare cell types with unprecedented resolution and accuracy. We are focusing on using single-cell multi-omics to characterise the phenotype and function of gut-resident and circulating immune cells in patients and matched controls. This unique dataset has identified several disease-associated populations which could potentially be targeted in novel therapies.

Melanie Dunstan (Project Lead), Ricardo FerreiraDominik Trzupek (Analysis Team)