Nature Immunology
6, 680 - 688 (2005)
Published online: 29 May 2005; | doi:10.1038/ni1209
Inhibitors of  -secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21Lisa M Minter1, 6, Danielle M Turley2, 6, Pritam Das3, Hyun Mu Shin1, Ila Joshi1, Rebecca G Lawlor1, Ok Hyun Cho1, Tanapat Palaga4, Sridevi Gottipati1, Janice C Telfer1, Lisa Kostura3, Abdul H Fauq3, Katherine Simpson3, Kimberly A Such1, Lucio Miele5, Todd E Golde3, Stephen D Miller2
& Barbara A Osborne11
Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, Massachusetts
01003, USA. 2
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
60611, USA. 3
Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, Jacksonville, Florida
32224, USA. 4
Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok
10330, Thailand. 5
Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois
60612, USA. 6
These authors contributed equally to this work.
Correspondence should be addressed to Barbara A Osborne osborne@vasci.umass.eduNotch receptors are processed by  -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, -secretase inhibitors extinguished expression of Notch, interferon- and Tbx21 in TH1-polarized CD4+ cells, whereas ectopic expression of activated Notch1 restored Tbx21 transcription. In vivo, administration of -secretase inhibitors substantially impeded TH1-mediated disease progression in the mouse experimental autoimmune encephalomyelitis model of multiple sclerosis. Thus, using -secretase inhibitors to modulate Notch signaling may prove beneficial in treating TH1-mediated autoimmunity.
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