title: The role of NF-kappaB and Smad3 in TGF-beta-mediated Foxp3 expression.
abstract: The transcription factor Foxp3 is essential for the development of functional, natural Treg (nTreg), which plays a prominent role in self-tolerance. Suppressive Foxp3(+) Treg cells can be generated from naïve T cells ex vivo, following TCR and TGF-beta1 stimulations. However, the molecular contributions from the different arms of these pathways leading to Foxp3 expression are not fully understood. TGF-beta1-activated Smad3 plays a major role in the expression of Foxp3, since TGF-beta1-induced-Treg generation from Smad3(-/-) mice is markedly reduced and abolished by inactivating Smad2. In the TCR pathway, deletion of Bcl10, which activates NF-kappaB, markedly reduces both IL-2 and Foxp3 production. However, partial rescue of Foxp3 expression occurs on addition of exogenous IL-2. TGF-beta1 significantly attenuates NF-kappaB binding to the Foxp3 promoter, while inducing Foxp3 expression. Furthermore, deletion of p50, a NF-kappaB subunit, results in increased Foxp3 expression despite a decline in the IL-2 production. We posit several TCR-NF-kappaB pathways, some increasing (Bcl10-IL-2-Foxp3) while others decreasing (p50-Foxp3) Foxp3 expression, with the former predominating. A better understanding of Foxp3 regulation could be useful in dissecting the cause of Treg dysfunction in several autoimmune diseases and for generating more potent TGF-beta1-induced-Treg cells for therapeutic purposes.
authors.affiliation: The Max McGee National Center for Juvenile Diabetes and Human Molecular Genetics Center, Medical College of Wisconsin and Children's Research Institute of Children's Hospital of Wisconsin, WI 53226, USA.
authors.forename: Srikanta
authors.initials: S
authors.lastname: Jana
authors.forename: Parthav
authors.initials: P
authors.lastname: Jailwala
authors.forename: Dipica
authors.initials: D
authors.lastname: Haribhai
authors.forename: Jill
authors.initials: J
authors.lastname: Waukau
authors.forename: Sanja
authors.initials: S
authors.lastname: Glisic
authors.forename: William
authors.initials: W
authors.lastname: Grossman
authors.forename: Manoj
authors.initials: M
authors.lastname: Mishra
authors.forename: Renren
authors.initials: R
authors.lastname: Wen
authors.forename: Demin
authors.initials: D
authors.lastname: Wang
authors.forename: Calvin B
authors.initials: CB
authors.lastname: Williams
authors.forename: Soumitra
authors.initials: S
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D052002:NF-kappa B p50 Subunit; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; C118258:SN50 peptide; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1