Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor

Immunity. 2009 Dec 18;31(6):921-31. doi: 10.1016/j.immuni.2009.09.022.


Naturally derived regulatory T (Treg) cells are characterized by stable expression of the transcription factor Foxp3 and characteristic epigenetic imprinting at the Foxp3 gene locus. Here, we found that enhancing nuclear factor (NF)-kappaB activity via a constitutive active inhibitor of kappaB kinase beta (IKKbeta) transgene in T cells led to increased number of Foxp3(+) cells in the thymus and can rescue Foxp3 expression in thymocytes deficient in other pleiotropic signaling molecules. Enhancing the signal strength of the NF-kappaB pathway also induced Foxp3 expression in otherwise conventionally selected T cells. NF-kappaB directly promoted the transcription of Foxp3, and upon T cell receptor (TCR) stimulation, c-Rel, a NF-kappaB family member, bound to Foxp3 enhancer region, which is specifically demethylated in natural Treg cells. Hence, NF-kappaB signaling pathway is a key regulator of Foxp3 expression during natural Treg cell development.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Animals
  • Base Sequence
  • CARD Signaling Adaptor Proteins / genetics
  • CARD Signaling Adaptor Proteins / metabolism
  • Forkhead Transcription Factors / genetics*
  • Genomic Imprinting*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • I-kappa B Proteins / metabolism*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • NF-kappa B / metabolism*
  • Proto-Oncogene Proteins c-rel / metabolism
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology*
  • Thymus Gland / immunology*


  • CARD Signaling Adaptor Proteins
  • Card11 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Homeodomain Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • Proto-Oncogene Proteins c-rel
  • RAG-1 protein
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7