IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells

Nat Immunol. 2008 Dec;9(12):1347-55. doi: 10.1038/ni.1677. Epub 2008 Nov 9.


Transcription factor Foxp3 is critical for generating regulatory T cells (T(reg) cells). Transforming growth factor-beta (TGF-beta) induces Foxp3 and suppressive T(reg) cells from naive T cells, whereas interleukin 6 (IL-6) inhibits the generation of inducible T(reg) cells. Here we show that IL-4 blocked the generation of TGF-beta-induced Foxp3(+) T(reg) cells and instead induced a population of T helper cells that produced IL-9 and IL-10. The IL-9(+)IL-10(+) T cells demonstrated no regulatory properties despite producing abundant IL-10. Adoptive transfer of IL-9(+)IL-10(+) T cells into recombination-activating gene 1-deficient mice induced colitis and peripheral neuritis, the severity of which was aggravated if the IL-9(+)IL-10(+) T cells were transferred with CD45RB(hi) CD4(+) effector T cells. Thus IL-9(+)IL-10(+) T cells lack suppressive function and constitute a distinct population of helper-effector T cells that promote tissue inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Cell Differentiation / immunology
  • Forkhead Transcription Factors / immunology*
  • Forkhead Transcription Factors / metabolism
  • GATA3 Transcription Factor / immunology
  • GATA3 Transcription Factor / metabolism
  • Interleukin-10 / immunology
  • Interleukin-10 / metabolism
  • Interleukin-4 / immunology*
  • Interleukin-4 / metabolism
  • Interleukin-9 / immunology
  • Interleukin-9 / metabolism
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Transgenic
  • STAT6 Transcription Factor / immunology
  • STAT6 Transcription Factor / metabolism
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • Transforming Growth Factor beta / immunology*
  • Transforming Growth Factor beta / metabolism


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Interleukin-9
  • STAT6 Transcription Factor
  • Transforming Growth Factor beta
  • Interleukin-10
  • Interleukin-4