Essential autocrine regulation by IL-21 in the generation of inflammatory T cells

Academic Article

Abstract

  • After activation, CD4+ helper T (TH) cells differentiate into distinct effector subsets that are characterized by their unique cytokine expression and immunoregulatory function. During this differentiation, TH1 and TH2 cells produce interferon-γ and interleukin (IL)-4, respectively, as autocrine factors necessary for selective lineage commitment. A distinct TH subset, termed THIL-17, TH17 or inflammatory TH (T Hi), has been recently identified as a distinct TH lineage mediating tissue inflammation. TH17 differentiation is initiated by transforming growth factor-Β and IL-6 (refs 5-7) and reinforced by IL-23 (ref. 8), in which signal transduction and activators of transcription (STAT)3 and retinoic acid receptor-related orphan receptor (ROR)-γ mediate the lineage specification. TH17 cells produce IL-17, IL-17F and IL-22, all of which regulate inflammatory responses by tissue cells but have no importance in TH17 differentiation. Here we show that IL-21 is another cytokine highly expressed by mouse TH17 cells. IL-21 is induced by IL-6 in activated T cells, a process that is dependent on STAT3 but not ROR-γ. IL-21 potently induces TH17 differentiation and suppresses Foxp3 expression, which requires STAT3 and ROR-γ, which is encoded by Rorc. IL-21 deficiency impairs the generation of TH17 cells and results in protection against experimental autoimmune encephalomyelitis. IL-21 is therefore an autocrine cytokine that is sufficient and necessary for TH17 differentiation, and serves as a target for treating inflammatory diseases. ©2007 Nature Publishing Group.
  • Published In

  • Nature  Journal
  • Digital Object Identifier (doi)

    Pubmed Id

  • 9219450
  • Author List

  • Nurieva R; Yang XO; Martinez G; Zhang Y; Panopoulos AD; Ma L; Schluns K; Tian Q; Watowich SS; Jetten AM
  • Start Page

  • 480
  • End Page

  • 483
  • Volume

  • 448
  • Issue

  • 7152