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PMID: 20439537 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells.

The Journal of experimental medicine ·Vol. 207 ·No. 7 ·2010-07-05 ·Pages 1381-91

Harada Y, Harada Y, Elly C, Ying G, Paik JH, DePinho RA, Liu YC

Abstract

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.

MeSH Terms
Adaptor Proteins, Signal Transducing/deficiency,metabolism Animals Cell Differentiation/genetics Forkhead Box Protein O1 Forkhead Box Protein O3 Forkhead Transcription Factors/genetics,metabolism Gene Expression Regulation Humans Jurkat Cells Lymphocyte Activation/genetics Mice Mice, Inbred C57BL Promoter Regions, Genetic/genetics Protein Binding Proto-Oncogene Proteins c-cbl/deficiency,metabolism Signal Transduction T-Lymphocytes, Regulatory/cytology,enzymology,metabolism
Chemicals
Adaptor Proteins, Signal Transducing Cblb protein, mouse Forkhead Box Protein O1 Forkhead Box Protein O3 Forkhead Transcription Factors FoxO3 protein, mouse Foxo1 protein, mouse Foxp3 protein, mouse Proto-Oncogene Proteins c-cbl
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Harada Yohsuke
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Harada Yasuyo
Elly Chris
Ying Ge
Paik Ji-Hye
DePinho Ronald A
Liu Yun-Cai
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20100004
Published
2010-07-05
Epub
2010-00-03
Pages
1381-91
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2901074
Subset
IM
Grants
NIAID NIH HHS · P01 AI089624 · United States
External Links
PubMed source DOI: 10.1084/jem.20100004 PMC Full Text View journal details
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