A new lineage of effector CD4 T cells?

A population of effector CD4 T cells characterized by the IL-23-induced production of IL-17 has been recently described and has been associated with autoimmunity in mouse and man. The development of IL-17 effectors has been associated with memory cell precursors and has been proposed to overlap with the Th1 lineage, although the precise mechanisms that control development of IL-17 effectors are undefined. Here we present data that argues against a shared developmental pathway with the Th1, or Th2, lineage and instead favors a distinct effector lineage, referred to as Th17. We show that the Th1 product, IFN-γ, potently inhibits the development of Th17 cells from naive precursors, whereas mature Th17 cells are resistant to suppression by IFN-γ. In the absence of IFN-γ, IL-23 acts on activated naive precursors to induce differentiation of Th17 cells. Further, Th17 development proceeds independently of STAT1, T-bet, STAT4 or STAT6. These findings provide a basis for understanding how inhibition of IFN-γ signaling leads to enhanced development of pathogenic Th17 effectors and disease exacerbation in autoimmunity.