CD4+ T cells producing interleukin 17 (IL-17) are associated with autoimmunity, although the precise mechanisms that control their development are undefined. Here we present data that challenge the idea of a shared developmental pathway with T helper type 1 (TH1) or TH2 lineages and instead favor the idea of a distinct effector lineage we call 'TH. The development of TH-17 cells from naive precursor cells was potently inhibited by interferon-γ (IFN-γ) and IL-4, whereas committed TH-17 cells were resistant to suppression by TH1 or TH2 cytokines. In the absence of IFN-γ and IL-4, IL-23 induced naive precursor cells to differentiate into TH-17 cells independently of the transcription factors STAT1, T-bet, STAT4 and STAT6. These findings provide a basis for understanding how inhibition of IFN-γ signaling enhances development of pathogenic TH-17 effector cells that can exacerbate autoimmunity. © 2005 Nature Publishing Group.