Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome.
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.
Ruan
Qingguo
Q
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Kameswaran
Vasumathi
V
Tone
Yukiko
Y
Li
Li
L
Liou
Hsiou-Chi
HC
Greene
Mark I
MI
Tone
Masahide
M
Chen
Youhai H
YH
D000818:Animals; D002454:Cell Differentiation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics* / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D051996:Transcription Factor RelA / Q000276:immunology* / Q000378:metabolism
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050778:NFATC Transcription Factors; D020569:Proto-Oncogene Proteins c-rel; C498144:Rela protein, mouse; D051785:Smad Proteins; D051996:Transcription Factor RelA