Inhibitors of gamma-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21.
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.
Minter
Lisa M
LM
Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, 01003, USA.
Turley
Danielle M
DM
Das
Pritam
P
Shin
Hyun Mu
HM
Joshi
Ila
I
Lawlor
Rebecca G
RG
Cho
Ok Hyun
OH
Palaga
Tanapat
T
Gottipati
Sridevi
S
Telfer
Janice C
JC
Kostura
Lisa
L
Fauq
Abdul H
AH
Simpson
Katherine
K
Such
Kimberly A
KA
Miele
Lucio
L
Golde
Todd E
TE
Miller
Stephen D
SD
Osborne
Barbara A
BA
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D016207:Cytokines / Q000276:immunology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D010450:Endopeptidases / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006968:Hypersensitivity, Delayed / Q000188:drug therapy / Q000276:immunology; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D011480:Protease Inhibitors / Q000494:pharmacology*; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000276:immunology; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D000098815:T-bet Transcription Factor
D016207:Cytokines; D004268:DNA-Binding Proteins; C497762:Notch1 protein, mouse; D011480:Protease Inhibitors; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse