Notchi and TGF 21 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cells

Jeremy B. Samon, Ameya Champhekar, Lisa M. Minter, Janice C. Telfer, Lucio Miele, Abdul Fauq, Pritam Das, Todd E. Golde, Barbara A. Osborne

Research output: Contribution to journalArticlepeer-review

154 Scopus citations

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 (TGFβ1) induces Foxp3 expression and a regulatory phenotype in peripheral T cells. Here, we show that pharmacologic inhibition of Notch signaling using γ-secretase inhibitor (GSI) treatment blocks (1) TGFβ1-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 Notchi, 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 TGFβ signaling and regulatory T cells. Together, these findings indicate that the Notch and TGFβ signaling pathways cooperatively regulate Foxp3 expression and regulatory T-cell maintenance both in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)1813-1821
Number of pages9
JournalBlood
Volume112
Issue number5
DOIs
StatePublished - Sep 1 2008

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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