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  Rapamycin-sensitive signals control TCR/CD28-driven Ifng, Il4 and Foxp3 transcription and promoter region methylation

Tomasoni, R., Basso, V., Pilipow, K., Sitia, G., Saccani, S., Alessandra, A., et al. (2011). Rapamycin-sensitive signals control TCR/CD28-driven Ifng, Il4 and Foxp3 transcription and promoter region methylation. European Journal of Immunology, 41, 2086-2096.

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Tomasoni, Romana, Autor
Basso, Veronica, Autor
Pilipow, Karolina, Autor
Sitia, Giovanni, Autor
Saccani, Simona1, Autor           
Alessandra, Agresti, Autor
Mietton, Flore, Autor
Natoli, Gioacchino, Autor
Colombetti, Sara, Autor
Mondino, Anna, Autor
Affiliations:
1Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243641              

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Schlagwörter: Cell differentiation; Cellular activation; Gene expression; T helper cells
 Zusammenfassung: The mammalian target of rapamycin (mTOR) controls T-cell differentiation in response to polarizing cytokines. We previously found that mTOR blockade by rapamycin (RAPA) delays the G1-S cell cycle transition and lymphocyte proliferation. Here, we report that both mTOR complex 1 and mTOR complex 2 are readily activated following TCR/CD28 engagement and are critical for early expression of Ifng, Il4 and Foxp3, and for effector T cell differentiation in the absence of polarizing cytokines. While inhibition of mTOR complex 1 and cell division were evident at low doses of RAPA, inhibition of mTOR complex 2, Ifng, Il4 and Foxp3 expression, and T-cell polarization required higher doses and more prolonged treatments. We found that while T-bet and GATA3 were readily induced following TCR/CD28 engagement, administration of RAPA delayed their expression, and interfered with the loss of DNA methylation within Ifng and Il4 promoter regions. In contrast, RAPA prevented activation-dependent DNA methylation of the Foxp3 promoter favoring Foxp3 expression. As a result, RAPA-cultured cells lacked immediate effector functions and instead were enriched for IL-2+ cells. We propose that mTOR-signaling, by timing the expression of critical transcription factors and DNA methylation of proximal promoter regions, regulates transcriptional competence at immunologically relevant sites and hence lymphocyte differentiation.

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Sprache(n): eng - English
 Datum: 2011
 Publikationsstatus: Erschienen
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: eDoc: 578643
 Art des Abschluß: -

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Titel: European Journal of Immunology
  Alternativer Titel : Eur. J. Immunol.
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 41 Artikelnummer: - Start- / Endseite: 2086 - 2096 Identifikator: -