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

229 Citations (Scopus)

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

Fingerprint

Amyloid Precursor Protein Secretases
Up-Regulation
Notch Receptors
T-Lymphocytes
Autoimmune Experimental Encephalomyelitis
T-Cell Antigen Receptor
Autoimmunity
Interferons
Multiple Sclerosis
Cues
Disease Progression
In Vitro Techniques

ASJC Scopus subject areas

  • Immunology

Cite this

Minter, L. M., Turley, D. M., Das, P., Shin, H. M., Joshi, I., Lawlor, R. G., ... 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/ni1209

Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. / Minter, Lisa M.; Turley, Danielle M.; Das, Pritam; Shin, Hyun Mu; Joshi, Ila; Lawlor, Rebecca G.; Cho, Ok Hyun; Palaga, Tanapat; Gottipati, Sridevi; Telfer, Janice C.; Kostura, Lisa; Fauq, Abdul H.; Simpson, Katherine; Such, Kimberly A.; Miele, Lucio; Golde, Todd E.; Miller, Stephen D.; Osborne, Barbara A.

In: Nature Immunology, Vol. 6, No. 7, 2005, p. 680-688.

Research output: Contribution to journalArticle

Minter, LM, Turley, DM, Das, P, Shin, HM, Joshi, I, Lawlor, RG, Cho, OH, Palaga, T, Gottipati, S, Telfer, JC, Kostura, L, Fauq, AH, Simpson, K, Such, KA, Miele, L, Golde, TE, Miller, SD & Osborne, BA 2005, 'Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21', Nature Immunology, vol. 6, no. 7, pp. 680-688. https://doi.org/10.1038/ni1209
Minter, Lisa M. ; Turley, Danielle M. ; Das, Pritam ; Shin, Hyun Mu ; Joshi, Ila ; Lawlor, Rebecca G. ; Cho, Ok Hyun ; Palaga, Tanapat ; Gottipati, Sridevi ; Telfer, Janice C. ; Kostura, Lisa ; Fauq, Abdul H. ; Simpson, Katherine ; Such, Kimberly A. ; Miele, Lucio ; Golde, Todd E. ; Miller, Stephen D. ; Osborne, Barbara A. / Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. In: Nature Immunology. 2005 ; Vol. 6, No. 7. pp. 680-688.
@article{75e9011a2935439a8a83e95474e718bd,
title = "Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21",
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.",
author = "Minter, {Lisa M.} and Turley, {Danielle M.} and Pritam Das and Shin, {Hyun Mu} and Ila Joshi and Lawlor, {Rebecca G.} and Cho, {Ok Hyun} and Tanapat Palaga and Sridevi Gottipati and Telfer, {Janice C.} and Lisa Kostura and Fauq, {Abdul H.} and Katherine Simpson and Such, {Kimberly A.} and Lucio Miele and Golde, {Todd E.} and Miller, {Stephen D.} and Osborne, {Barbara A.}",
year = "2005",
doi = "10.1038/ni1209",
language = "English (US)",
volume = "6",
pages = "680--688",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21

AU - Minter, Lisa M.

AU - Turley, Danielle M.

AU - Das, Pritam

AU - Shin, Hyun Mu

AU - Joshi, Ila

AU - Lawlor, Rebecca G.

AU - Cho, Ok Hyun

AU - Palaga, Tanapat

AU - Gottipati, Sridevi

AU - Telfer, Janice C.

AU - Kostura, Lisa

AU - Fauq, Abdul H.

AU - Simpson, Katherine

AU - Such, Kimberly A.

AU - Miele, Lucio

AU - Golde, Todd E.

AU - Miller, Stephen D.

AU - Osborne, Barbara A.

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=22144492615&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=22144492615&partnerID=8YFLogxK

U2 - 10.1038/ni1209

DO - 10.1038/ni1209

M3 - Article

C2 - 15991363

AN - SCOPUS:22144492615

VL - 6

SP - 680

EP - 688

JO - Nature Immunology

JF - Nature Immunology

SN - 1529-2908

IS - 7

ER -