The molecular basis of IL-21-mediated proliferation

Blood. 2007 May 15;109(10):4135-42. doi: 10.1182/blood-2006-10-054973. Epub 2007 Jan 18.


Interleukin-21 (IL-21) is a type I cytokine that modulates functions of T, B, natural killer (NK), and myeloid cells. The IL-21 receptor (IL-21R) is closely related to the IL-2 receptor beta chain and is capable of transducing signals through its dimerization with the common cytokine receptor gamma chain (gamma(c)), the protein whose expression is defective in humans with X-linked severe combined immunodeficiency. To clarify the molecular basis of IL-21 actions, we investigated the role of tyrosine residues in the IL-21R cytoplasmic domain. Simultaneous mutation of all 6 tyrosines greatly diminished IL-21-mediated proliferation, whereas retention of tyrosine 510 (Y510) allowed full proliferation. Y510 efficiently mediated IL-21-induced phosphorylation of Stat1 and Stat3, but not of Stat5, and CD8(+) T cells from Stat1/Stat3 double knock-out mice exhibited decreased proliferation in response to IL-21 + IL-15. In addition, IL-21 weakly induced phosphorylation of Shc and Akt, and consistent with this, specific inhibitors of the MAPK and PI3K pathways inhibited IL-21-mediated proliferation. Collectively, these data indicate the involvement of the Jak-STAT, MAPK, and PI3K pathways in IL-21 signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Interleukin-15 / pharmacology
  • Interleukins / pharmacology*
  • Lymphocyte Activation / drug effects*
  • Lymphocyte Activation / genetics
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Phosphatidylinositol 3-Kinases / physiology
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Tyrosine / physiology


  • Interleukin-15
  • Interleukins
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Stat1 protein, mouse
  • Stat3 protein, mouse
  • Tyrosine
  • Phosphatidylinositol 3-Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • interleukin-21