Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome

Immunity. 2009 Dec 18;31(6):932-40. doi: 10.1016/j.immuni.2009.10.006.


Regulatory T (Treg) cells are essential for maintaining immune homeostasis. Although Foxp3 expression marks the commitment of progenitors to Treg cell lineage, how Treg cells are generated during lymphocyte development remains enigmatic. We report here that the c-Rel transcription factor controlled development of Treg cells by promoting the formation of a Foxp3-specific enhanceosome. This enhanceosome contained c-Rel, p65, NFAT, Smad, and CREB. Although Smad and CREB first bound to Foxp3 enhancers, they later moved to the promoter to form the c-Rel enhanceosome. c-Rel-deficient mice had up to 90% reductions of Treg cells compared to wild-type mice, and c-Rel-deficient T cells were compromised in Treg cell differentiation. Thus, Treg cell development is controlled by a c-Rel enhanceosome, and strategies targeting Rel-NF-kappaB can be effective for manipulating Treg cell function.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Forkhead Transcription Factors / genetics*
  • Gene Expression Regulation*
  • Mice
  • Mice, Inbred C57BL
  • NFATC Transcription Factors / metabolism
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-rel / genetics*
  • Proto-Oncogene Proteins c-rel / metabolism
  • Smad Proteins / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • Transcription Factor RelA / immunology*
  • Transcription Factor RelA / metabolism


  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • NFATC Transcription Factors
  • Proto-Oncogene Proteins c-rel
  • Rela protein, mouse
  • Smad Proteins
  • Transcription Factor RelA