The cytokine TGF-β co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells

Nat Immunol. 2014 Sep;15(9):856-65. doi: 10.1038/ni.2947. Epub 2014 Jul 27.


Understanding the developmental mechanisms of follicular helper T cells (TFH cells) in humans is relevant to the clinic. However, the factors that drive the differentiation of human CD4+ helper T cells into TFH cells remain largely undefined. Here we found that transforming growth factor-β (TGF-β) provided critical additional signals for the transcription factors STAT3 and STAT4 to promote initial TFH differentiation in humans. This mechanism did not appear to be shared by mouse helper T cells. Developing human TFH cells that expressed the transcriptional repressor Bcl-6 also expressed RORγt, a transcription factor typically expressed by the TH17 subset of helper T cells. Our study documents a mechanism by which TFH cells and TH17 cells emerge together in inflammatory environments in humans, as is often observed in many human autoimmune diseases.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / immunology*
  • DNA-Binding Proteins / immunology
  • Germinal Center / immunology*
  • Humans
  • Mice
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
  • Proto-Oncogene Proteins c-bcl-6
  • STAT3 Transcription Factor / immunology*
  • STAT4 Transcription Factor / immunology*
  • Signal Transduction / immunology*
  • T-Lymphocytes, Helper-Inducer / immunology*
  • Th17 Cells / immunology*
  • Transforming Growth Factor beta


  • BCL6 protein, human
  • DNA-Binding Proteins
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Proto-Oncogene Proteins c-bcl-6
  • RORC protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • STAT4 Transcription Factor
  • STAT4 protein, human
  • Stat3 protein, mouse
  • Stat4 protein, mouse
  • Transforming Growth Factor beta