Composition and functional heterogeneity of naïve-like T cells in primary sclerosing cholangitis (PSC)

• Applicant: Dr. Dorothee Schwinge
• Subject Area: Gastroenterology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 528954476

Primary sclerosing cholangitis (PSC) is an enigmatic liver disease characterized by a chronic inflammation leading to scarring and obliteration of intra- and extrahepatic bile ducts. There is no licenced pharmacological treatment with a proven benefit on the disease course, leading PSC as major cause for liver transplantation in the western world. The pathogenesis is largely unknown but it is widely believed that PSC is an immune mediated disease with environmental and genetic factors contributing to immune dysregulation. We and others have previously revealed changes in frequencies and function of T cell subsets in people with PSC. Briefly, we found reduced frequencies and function of regulatory T cells (TREG) in blood and liver of people with PSC. Moreover, we observed increased frequencies of TH17 cells after in vitro stimulation with pathogens and following ex vivo stimulation with PMA/Ionomycin and identified monocytes as potential mediators of Th17 differentiation. Recently, we generated the first single-cell atlas of intrahepatic T cells from human livers obtained from people suffering from PSC and identified a population of CD4+ T cells, which displayed distinct patterns of both gene and surface protein expression. Due to the unusual location of these cells bearing several aspects of naïvety despite residing within non-lymphoid tissue, we termed them ‘naïve-like’ CD4+ T cells. After identifying a significant part (38.6%) of these cells to be tissue-resident, we examined the function of the naïve-like CD4+ T cells. We could show that these intrahepatic naive-like population of CD4+ T cells in people with PSC is prone to polarize towards a pro-inflammatory TH17 phenotype. However, the mechanisms causing misguided immune cell differentiation are poorly understood. Previously, several genome-wide association studies (GWAS) have associated PSC to polymorphisms related to immune cell- and particularly T cell-function (e.g. IL2RA, BACH2, FOXP1, CD28) but only few studies have so far reported on the functional implications of these polymorphisms. BACH2 has been shown to be a critical TF for differentiation and maturation in both T and B lymphocytes and it has been described to regulates networks of genes that control effector T cell lineages and thereby limit the differentiation into effector T cells and promote the development of FoxP3+ regulatory T cells (Treg cells). Importantly, we found carriers of rs56258221 (BACH2) and non-carriers to significantly differ using our in vitro polarization assays. Following these findings leading to our central hypotheses that (I) the pathogenic CD4+ T cell response in PSC is the result of disordered T cell differentiation and that (II) several genetic risk factors associated with PSC are major determinants of this misguided CD4+ T cell differentiation. The detailed analysis of naïve T cells will therefore reveal novel treatment targets for a disease that is currently without any effective therapy.

• DFG Programme: Research Grants