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

Romana Tomasoni, Veronica Basso, Karolina Pilipow, Giovanni Sitia, Simona Saccani, Alessandra Agresti, Flore Mietton, Gioacchino Natoli, Sara Colombetti, Anna Mondino

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)2086-2096
Number of pages11
JournalEuropean Journal of Immunology
Volume41
Issue number7
DOIs
Publication statusPublished - Jul 2011

Keywords

  • Cell differentiation
  • Cellular activation
  • Gene expression
  • T helper cells

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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