Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells.
The transcription factor Foxp3 is essential for optimal regulatory T (T reg) cell development and function. Here, we show that CD4(+) T cells from Cbl-b RING finger mutant knockin or Cbl-b-deficient mice show impaired TGF-beta-induced Foxp3 expression. These T cells display augmented Foxo3a phosphorylation, but normal TGF-beta signaling. Expression of Foxo3a rescues Foxp3 expression in Cbl-b-deficient T cells, and Foxo3a deficiency results in defective TGF-beta-driven Foxp3 induction. A Foxo3a-binding motif is present in a proximal region of the Foxp3 promoter, and is required for Foxo3a association. Foxo1 exerts similar effects as Foxo3a on Foxp3 expression. This study reveals that Foxo factors promote transcription of the Foxp3 gene in induced T reg cells, and thus provides new mechanistic insight into Foxo-mediated T cell regulation.
Harada
Yohsuke
Y
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Harada
Yasuyo
Y
Elly
Chris
C
Ying
Ge
G
Paik
Ji-Hye
JH
DePinho
Ronald A
RA
Liu
Yun-Cai
YC
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; C498833:Foxp3 protein, mouse; D050721:Proto-Oncogene Proteins c-cbl