Abstract
Notch receptors are processed by gamma-secretase acting in synergy with T cell receptor signaling to sustain peripheral T cell activation. Activated CD4+ T cells differentiate into T helper type 1 (TH1) or TH2 subsets. Molecular cues directing TH1 differentiation include expression of the TH1-specific transcription factor T-bet, encoded by Tbx21. However, the regulation of Tbx21 remains incompletely defined. Here we report that Notch1 can directly regulate Tbx21 through complexes formed on the Tbx21 promoter. In vitro, gamma-secretase inhibitors extinguished expression of Notch, interferon-gamma and Tbx21 in TH1-polarized CD4+ cells, whereas ectopic expression of activated Notch1 restored Tbx21 transcription. In vivo, administration of gamma-secretase inhibitors substantially impeded TH1-mediated disease progression in the mouse experimental autoimmune encephalomyelitis model of multiple sclerosis. Thus, using gamma-secretase inhibitors to modulate Notch signaling may prove beneficial in treating TH1-mediated autoimmunity.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Amyloid Precursor Protein Secretases
-
Animals
-
Aspartic Acid Endopeptidases
-
Cytokines / immunology
-
DNA-Binding Proteins / antagonists & inhibitors*
-
DNA-Binding Proteins / biosynthesis
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / immunology
-
Encephalomyelitis, Autoimmune, Experimental / drug therapy
-
Encephalomyelitis, Autoimmune, Experimental / enzymology
-
Encephalomyelitis, Autoimmune, Experimental / immunology
-
Endopeptidases / immunology*
-
Enzyme-Linked Immunosorbent Assay
-
Female
-
Hypersensitivity, Delayed / drug therapy
-
Hypersensitivity, Delayed / immunology
-
Immunoblotting
-
Mice
-
Mice, Inbred C57BL
-
Protease Inhibitors / pharmacology*
-
Receptor, Notch1
-
Receptors, Cell Surface / antagonists & inhibitors*
-
Receptors, Cell Surface / immunology
-
T-Box Domain Proteins
-
T-bet Transcription Factor
-
Th1 Cells / drug effects
-
Th1 Cells / enzymology
-
Th1 Cells / immunology*
-
Transcription Factors / antagonists & inhibitors*
-
Transcription Factors / biosynthesis
-
Transcription Factors / genetics
-
Transcription Factors / immunology
-
Up-Regulation / drug effects
-
Up-Regulation / immunology
Substances
-
Cytokines
-
DNA-Binding Proteins
-
Notch1 protein, mouse
-
Protease Inhibitors
-
Receptor, Notch1
-
Receptors, Cell Surface
-
T-Box Domain Proteins
-
T-bet Transcription Factor
-
Transcription Factors
-
Amyloid Precursor Protein Secretases
-
Endopeptidases
-
Aspartic Acid Endopeptidases
-
Bace1 protein, mouse