008 Metabolic and functional dysregulation of tissue-specific human regulatory T cells in chronic inflammatory diseases

Regulatory T cells (T_reg) are a critical immune component guarding against excessive inflammatory responses, but current understanding of T_reg heterogeneity and function in non-lymphoid tissue in humans is limited. In this project we are characterising unique types of T_reg signatures in the context of tissue-confined inflammatory responses in human skin and gut. We are hypothesising that a common ground between these pathologies may be found in a dysfunction of immune regulation. To investigate this, we are utilizing transcriptomic, phenotypic and metabolomic methods, using an integrative bioinformatical approach of single-cell (sc) sequencing data and global metabolomic screens of T_regs from blood and tissue of patients with chronic inflammatory diseases. ScRNA-sequencing data from patients diagnosed with psoriasis, chronic cutaneous sarcoidosis, and ulcerative colitis have shown that diseased tissue-T_regs have a strong tissue-resident signature. We found an exacerbated expression of polyamine catabolic genes linked to a more activated phenotype of T_reg compared to their healthy counterparts. Additionally, we performed untargeted metabolomics of blood-derived T_regs, identifying further changes in metabolites downstream of several nitrogen metabolic pathways and nucleotide synthesis. Together, our results indicate a novel interface of polyamine catabolism and pyrimidine synthesis found in tissue T_regs in chronic inflammation. Ultimately, our findings will significantly contribute to basic understanding of T_reg function and shed light on immune regulation during chronic inflammation.