Inhibitors of γ-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 ( T(H)1) or T(H)2 subsets. Molecular cues directing TH1 differentiation include expression of the T(H)1-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 T(H)1-polarized CD4(+) cells, whereas ectopic expression of activated Notch1 restored Tbx21 transcription. In vivo, administration of gamma-secretase inhibitors substantially impeded T(H)1-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 T(H)1-mediated autoimmunity.