Nonredundant roles for Stat5a/b in directly regulating Foxp3.
Stats (signal transducers and activators of transcription) regulate multiple aspects of T-cell fate. T regulatory (Treg) cells are a critical subset that limits immune responses, but the relative importance of Stat5a/b versus Stat3 for Treg cell development has been contentious. We observed that peripheral CD25(+)CD4(+) T cells were reduced in Stat5(DeltaN) mice; however, the levels of Foxp3, a transcription factor that is critical for Treg cells, were normal in splenic CD4(+) T cells even though they were reduced in the thymus. In contrast, complete deletion of Stat5a/b (Stat5(-/-)) resulted in dramatic reduction in CD25- or Foxp3-expressing CD4(+) T cells. An intrinsic requirement was demonstrated by reduction of Stat5a/b in CD4-expressing cells and by stem cell transplantation using Stat5(-/-) fetal liver cells. Stat5a/b were also required for optimal induction of Foxp3 in vitro and bound directly to the Foxp3 gene. Reduction of Stat3 in T cells did not reduce the numbers of Treg cells in the thymus or spleen; however, Stat3 was required for IL-6-dependent down-regulation of Foxp3. Therefore, we conclude that Stat5a/b have an essential, nonredundant role in regulating Treg cells, and that Stat3 and Stat5a/b appear to have opposing roles in the regulation of Foxp3.
Yao
Zhengju
Z
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1820, USA.
Kanno
Yuka
Y
Kerenyi
Marc
M
Stephens
Geoffrey
G
Durant
Lydia
L
Watford
Wendy T
WT
Laurence
Arian
A
Robinson
Gertraud W
GW
Shevach
Ethan M
EM
Moriggl
Richard
R
Hennighausen
Lothar
L
Wu
Changyou
C
O'Shea
John J
JJ
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D038041:Lymphopoiesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D050796:STAT3 Transcription Factor / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000502:physiology*; D012689:Sequence Homology, Nucleic Acid; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse