Abstract| Volume 142, ISSUE 12, SUPPLEMENT , S182, December 2022

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

      Regulatory T cells (Treg) are a critical immune component guarding against excessive inflammatory responses, but current understanding of Treg heterogeneity and function in non-lymphoid tissue in humans is limited. In this project we are characterising unique types of Treg 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 Tregs 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-Tregs have a strong tissue-resident signature. We found an exacerbated expression of polyamine catabolic genes linked to a more activated phenotype of Treg compared to their healthy counterparts. Additionally, we performed untargeted metabolomics of blood-derived Tregs, 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 Tregs in chronic inflammation. Ultimately, our findings will significantly contribute to basic understanding of Treg function and shed light on immune regulation during chronic inflammation.