| First Author | Jana S | Year | 2009 |
| Journal | Eur J Immunol | Volume | 39 |
| Issue | 9 | Pages | 2571-83 |
| PubMed ID | 19701891 | Mgi Jnum | J:152150 |
| Mgi Id | MGI:4356358 | Doi | 10.1002/eji.200939201 |
| Citation | Jana S, et al. (2009) The role of NF-kappaB and Smad3 in TGF-beta-mediated Foxp3 expression. Eur J Immunol 39(9):2571-83 |
| abstractText | 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 naive 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. |
