Investigating the role of the transcription factor TCF-1 in the tissue adaptation of Th17 cells in renal autoimmune disease

Abstract

Chronic kidney diseases affect approximately 10-12% of the world population and ranks among the top ten causes of death globally. One of these kidney diseases is crescentic glomerulonephritis which accounts for 15% of these patients in severe cases leading to irreversible kidney failure. CD4+ T cells, Th17 cells in particular, are key drivers of immune mediated renal tissue damage. Th17 cells have shown to exhibit tissue adaptation capabilities, potentially worsening or ameliorating the disease outcome.

In this study, the role of the transcription factor, TCF-1, in the plasticity of Th17 cells was investigated. Using Il17Acre x R26eYFP and Tcf7flox x Il17Acre x R26eYFP mouse lines in in vivo experiments, it was revealed that in the absence of TCF-1 renal IL-17A producing cells produce more of the anti-inflammatory cytokine IL-10. Additionally, single cell RNA sequencing revealed the heterogeneity of Th17 cells by identifying various subsets of renal Th17 cells with different cytokine expression profiles. Furthermore, a pseudotime analysis using the single cell data of the renal Th17 cells revealed an inverse relationship of the expression of the transcription factors TCF-1 and RORγT, revealing TCF-1 to be a negative regulator of renal Th17 cells.

These findings could potentially lead to discovering more strategic and efficient therapeutic approaches in crescentic glomerulonephritis by targeting pathogenic Th17 cells, triggering an anti-inflammatory response in the kidney to avoid further tissue damage.