Faculty Collaboration Database

The role of NF-kappaB and Smad3 in TGF-beta-mediated Foxp3 expression. Eur J Immunol 2009 Sep;39(9):2571-83

Date

08/25/2009

Pubmed ID

19701891

DOI

10.1002/eji.200939201

Scopus ID

2-s2.0-70349243737 (requires institutional sign-in at Scopus site)   45 Citations

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.

Author List

Jana S, Jailwala P, Haribhai D, Waukau J, Glisic S, Grossman W, Mishra M, Wen R, Wang D, Williams CB, Ghosh S

Author

Calvin B. Williams MD, PhD Chief, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
CD4-Positive T-Lymphocytes
Cells, Cultured
Forkhead Transcription Factors
Interleukin-2
Mice
Mice, Inbred C57BL
NF-kappa B p50 Subunit
Peptides
Receptors, Antigen, T-Cell
Smad3 Protein
T-Lymphocytes, Regulatory
Transforming Growth Factor beta1