The TCF-1-E-protein axis preserves stem-like Th17 identity and prevents autoimmune pathology

T helper 17 (Th17) cells exhibit plasticity, transitioning from homeostatic cells to pathogenic effectors in autoimmune diseases. Although TCF-1 restrains Th17 pathogenicity by binding RORγt, mechanisms sustaining TCF-1 expression in mature Th17 cells and the transcriptional architecture governing the switch between states remain unknown. Using an interleukin 17 (IL-17) fate-mapping system deleting Tcf7 in cells with IL-17 history, we show that TCF-1 maintains homeostatic Th17 identity. TCF-1 deficiency does not impair Th17 generation but destabilizes the non-pathogenic state, causing loss of stem-like markers (SLAMF6 and CD27), acquisition of pathogenic features (CXCR6, T-bet, and IFN-γ), and exacerbated experimental autoimmune encephalomyelitis. Mechanistically, TCF-1 and E-proteins form a reciprocal feedback loop establishing a self-reinforcing transcriptional circuit; disruption of either collapses this circuit and unleashes pathogenicity. Single-cell transcriptomics reveals that TCF-1 downregulation is an early event in pathogenic conversion. Thus, the TCF-1-E-protein axis sustains TCF-1 expression and prevents pathogenic conversion.