Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21

Lisa M. Minter, Danielle M. Turley, Pritam Das, Hyun Mu Shin, Ila Joshi, Rebecca G. Lawlor, Ok Hyun Cho, Tanapat Palaga, Sridevi Gottipati, Janice C. Telfer, Lisa Kostura, Abdul H. Fauq, Katherine Simpson, Kimberly A. Such, Lucio Miele, Todd E. Golde, Stephen D. Miller, Barbara A. Osborne

Research output: Contribution to journalArticle

238 Scopus citations

Abstract

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 (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, γ-secretase inhibitors extinguished expression of Notch, interferon-γ and Tbx21 in TH1-polarized CD4+ cells, whereas ectopic expression of activated Notch1 restored Tbx21 transcription. In vivo, administration of γ-secretase inhibitors substantially impeded TH1-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 TH1-mediated autoimmunity.

Original languageEnglish (US)
Pages (from-to)680-688
Number of pages9
JournalNature immunology
Volume6
Issue number7
DOIs
StatePublished - 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Minter, L. M., Turley, D. M., Das, P., Shin, H. M., Joshi, I., Lawlor, R. G., Cho, O. H., Palaga, T., Gottipati, S., Telfer, J. C., Kostura, L., Fauq, A. H., Simpson, K., Such, K. A., Miele, L., Golde, T. E., Miller, S. D., & Osborne, B. A. (2005). Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. Nature immunology, 6(7), 680-688. https://doi.org/10.1038/ni1209x