ã-secretase inhibitors block in vivo and in vitro Th1 polarization by preventing Notch upregulation of t-betNature Immunology (2005)
AbstractNotch 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 DateJuly, 2005
Citation InformationBarbara A. Osborne. "ã-secretase inhibitors block in vivo and in vitro Th1 polarization by preventing Notch upregulation of t-bet" Nature Immunology Vol. 6 Iss. 7 (2005)
Available at: http://works.bepress.com/barbara_osborne/77/