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 γ-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_H1) or T_H2 subsets. Molecular cues directing T_H1 differentiation include expression of the T_H1-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, γ-secretase inhibitors extinguished expression of Notch, interferon-γ and Tbx21 in T_H1-polarized CD4⁺ cells, whereas ectopic expression of activated Notch1 restored Tbx21 transcription. In vivo, administration of γ-secretase inhibitors substantially impeded T_H1-mediated disease progression in the mouse experimental autoimmune encephalomyelitis model of multiple sclerosis. Thus, using γ-secretase inhibitors to modulate Notch signaling may prove beneficial in treating T_H1-mediated autoimmunity.