Smad3 binding to the foxp3 enhancer is dispensable for the development of regulatory T cells with the exception of the gut.
Regulatory T cells (T reg cells) are essential for the prevention of autoimmunity throughout life. T reg cell development occurs intrathymically but a subset of T reg cells can also differentiate from naive T cells in the periphery. In vitro, Smad signaling facilitates conversion of naive T cells into T reg cells but results in unstable Foxp3 expression. The TGF-β-Smad response element in the foxp3 locus is located in the CNS1 region in close proximity to binding sites for transcription factors implicated in TCR and retinoic acid signaling. From in vitro experiments it was previously postulated that foxp3 transcription represents a hierarchical process of transcription factor binding in which Smad3 would play a central role in transcription initiation. However, in vitro conditions generate T reg cells that differ from T reg cells encountered in vivo. To address the relevance of Smad3 binding to the CNS1 enhancer in vivo, we generated mice that exclusively lack the Smad binding site (foxp3(CNS1mut)). We show that binding of Smad3 to the foxp3 enhancer is dispensable for T reg cell development in newborn and adult mice with the exception of the gut.
Laboratory of Lymphocyte Biology, Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA 02115, USA.
Susan M
SM
Schlenner
Benno
B
Weigmann
Qingguo
Q
Ruan
Youhai
Y
Chen
Harald
H
von Boehmer
D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D003092:Colitis / Q000276:immunology; D004742:Enhancer Elements, Genetic; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000166:cytology / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta