The role of NF-kappaB and Smad3 in TGF-beta-mediated Foxp3 expression.
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.
Jana
Srikanta
S
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.
Jailwala
Parthav
P
Haribhai
Dipica
D
Waukau
Jill
J
Glisic
Sanja
S
Grossman
William
W
Mishra
Manoj
M
Wen
Renren
R
Wang
Demin
D
Williams
Calvin B
CB
Ghosh
Soumitra
S
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
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