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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4368-4375.
Prepublished online as a Blood First Edition Paper on January 16, 2007; DOI 10.1182/blood-2006-11-055756.


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IMMUNOBIOLOGY

Nonredundant roles for Stat5a/b in directly regulating Foxp3

Zhengju Yao1,2, Yuka Kanno1, Marc Kerenyi4, Geoffrey Stephens5, Lydia Durant1, Wendy T. Watford1, Arian Laurence1, Gertraud W. Robinson6, Ethan M. Shevach5, Richard Moriggl3, Lothar Hennighausen6, Changyou Wu2, and John J. O'Shea1

1 Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD; 2 Department of Immunology, Zhongshan Medical School, Sun Yat-Sen University, China; 3 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria; 4 Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University of Vienna (MUW), Austria; 5 Laboratory of Immunology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD; 6 Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD

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{Delta}N 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.


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