|Title||Inhibitors of gamma-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21.|
|Publication Type||Journal Article|
|Year of Publication||2005|
|Authors||Minter, LM, Turley, DM, Das, P, Shin, HMu, Joshi, I, Lawlor, RG, Cho, OHyun, Palaga, T, Gottipati, S, Telfer, JC, Kostura, L, Fauq, AH, Simpson, K, Such, KA, Miele, L, Golde, TE, Miller, SD, Osborne, BA|
|Date Published||2005 Jul|
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.
|Alternate Journal||Nat. Immunol.|