Abstract:
:Notch and its ligands have been implicated in the regulation and differentiation of various CD4(+) T-helper cells. Regulatory T cells (T(regs)), which express the transcription factor Foxp3, suppress aberrant immune responses that are typically associated with autoimmunity or excessive inflammation. Previous studies have shown that transforming growth factor beta (TGFbeta1) induces Foxp3 expression and a regulatory phenotype in peripheral T cells. Here, we show that pharmacologic inhibition of Notch signaling using gamma-secretase inhibitor (GSI) treatment blocks (1) TGFbeta1-induced Foxp3 expression, (2) the up-regulation of Foxp3-target genes, and (3) the ability to suppress naive T-cell proliferation. In addition, the binding of Notch1, CSL, and Smad to conserved binding sites in the foxp3 promoter can be inhibited by treatment with GSI. Finally, in vivo administration of GSI results in reduced Foxp3 expression and development of symptoms consistent with autoimmune hepatitis, a disease previously found to result from dysregulation of TGFbeta signaling and regulatory T cells. Together, these findings indicate that the Notch and TGFbeta signaling pathways cooperatively regulate Foxp3 expression and regulatory T-cell maintenance both in vitro and in vivo.
journal_name
Bloodjournal_title
Bloodauthors
Samon JB,Champhekar A,Minter LM,Telfer JC,Miele L,Fauq A,Das P,Golde TE,Osborne BAdoi
10.1182/blood-2008-03-144980subject
Has Abstractpub_date
2008-09-01 00:00:00pages
1813-21issue
5eissn
0006-4971issn
1528-0020pii
blood-2008-03-144980journal_volume
112pub_type
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