Identification of Th17 Cells with Stemness Features in Crescentic Glomerulonephritis

Background: Th17 cells are key drivers of autoimmune diseases, but how they persist in renal autoimmunity remains unclear. The role of stem-like Th17 cells in this context has not been explored so far. Here, we explore Th17 cell heterogeneity, function and differentiation in ANCA-associated glomerulonephritis (ANCA-GN) and in experimental GN. Methods: We performed scRNA-seq and flow cytometry on kidney and blood samples from ANCA-GN patients, experimental crescentic GN (nephrotoxic nephritis, NTN) model and mouse Staphylococcus aureus (S. aureus) infection to profile Th17 subsets. Adoptive transfer of SLAMF6+ and SLAMF6- Th17 cells from NTN mice into Rag1-/- recipients assessed self-renewal and pathogenicity. Single-cell trajectory analyses and adoptive transfers in the infection model evaluated Th17 differentiation. IL-17ACre × Tcf7fl/fl conditional knockout mice tested transcriptional regulation. IL-7 stimulation of patient Th17 cells was performed in vitro. Results: From the kidney of ANCA-GN patients, we identified stem-like Th17 with high TCF7 expression and tissue-resident memory Trm17 cells. Transferred stem-like SLAMF6+ Th17 cells from NTN mice maintained self-renewal capacity in Rag1-/-recipients. Single-cell trajectory analysis in both human ANCA-GN and mouse models revealed a differentiation pathway from stem-like Th17 to Trm17 cells. Notably, SLAMF6+ Th17 cells gave rise to CXCR6+CD69+ Trm17 cells in Rag1-/- recipients with S. aureus infection. Conditional deletion of TCF7 in IL17ACre Tcf7fl/fl mice reduced both Th17 subsets, impaired cytokine production, and suppressed proliferation, indicating a functional role of TCF7 in Th17 cell maintenance. Conclusion: Stem-like Th17 cells show TCF7-dependent self-renewal and differentiation into Trm17 cells and thereby might contribute to autoimmune kidney. The IL-7/CXCR6 axis may promote tissue retention, identifying potential therapeutic targets in renal autoimmunity. Funding: Government Support – Non-U.S.