Smad2 positively regulates the generation of Th17 cells

J Biol Chem. 2010 Sep 17;285(38):29039-43. doi: 10.1074/jbc.C110.155820. Epub 2010 Jul 28.

Abstract

Development of Foxp3(+) regulatory T cells and pro-inflammatory Th17 cells from naive CD4(+) T cells requires transforming growth factor-β (TGF-β) signaling. Although Smad4 and Smad3 have been previously shown to regulate Treg cell induction by TGF-β, they are not required in the development of Th17 cells. Thus, how TGF-β regulates Th17 cell differentiation remains unclear. In this study, we found that TGF-β-induced Foxp3 expression was significantly reduced in the absence of Smad2. More importantly, Smad2 deficiency led to reduced Th17 differentiation in vitro and in vivo. In the experimental autoimmune encephalomyelitis model, Smad2 deficiency in T cells significantly ameliorated disease severity and reduced generation of Th17 cells. Furthermore, we found that Smad2 associated with retinoid acid receptor-related orphan receptor-γt (RORγt) and enhanced RORγt-induced Th17 cell generation. These results demonstrate that Smad2 positively regulates the generation of inflammatory Th17 cells.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Line
  • Cells, Cultured
  • Disease Models, Animal
  • Encephalomyelitis / genetics
  • Encephalomyelitis / immunology
  • Encephalomyelitis / metabolism
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression / drug effects
  • Humans
  • Immunoprecipitation
  • Interleukin-17 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Orphan Nuclear Receptors / genetics
  • Orphan Nuclear Receptors / metabolism
  • Protein Binding / genetics
  • Protein Binding / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Smad2 Protein / genetics
  • Smad2 Protein / metabolism*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes, Helper-Inducer / cytology*
  • T-Lymphocytes, Helper-Inducer / immunology*
  • Transforming Growth Factor beta / pharmacology

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-17
  • Orphan Nuclear Receptors
  • Smad2 Protein
  • Transforming Growth Factor beta