Notch1 and TGFbeta1 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cells.
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.
Program in Animal Biotechnology and Biomedical Science, University of Massachusetts Amherst, MA 01003, USA.
Jeremy B
JB
Samon
Ameya
A
Champhekar
Lisa M
LM
Minter
Janice C
JC
Telfer
Lucio
L
Miele
Abdul
A
Fauq
Pritam
P
Das
Todd E
TE
Golde
Barbara A
BA
Osborne
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001483:Base Sequence; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology / Q000502:physiology*
D001381:Azepines; D017931:DNA Primers; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D009124:Muscle Proteins; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; C497762:Notch1 protein, mouse; D011480:Protease Inhibitors; D051881:Receptor, Notch1; D051785:Smad Proteins; C499035:Smpx protein, mouse; D053773:Transforming Growth Factor beta1; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine