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 language | English |
|---|---|
| Pages (from-to) | 2086-2096 |
| Number of pages | 11 |
| Journal | European Journal of Immunology |
| Volume | 41 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Jul 2011 |
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Keywords
- Cell differentiation
- Cellular activation
- Gene expression
- T helper cells
ASJC Scopus subject areas
- Immunology
- Immunology and Allergy
Cite this
Rapamycin-sensitive signals control TCR/CD28-driven Ifng, Il4 and Foxp3 transcription and promoter region methylation. / Tomasoni, Romana; Basso, Veronica; Pilipow, Karolina; Sitia, Giovanni; Saccani, Simona; Agresti, Alessandra; Mietton, Flore; Natoli, Gioacchino; Colombetti, Sara; Mondino, Anna.
In: European Journal of Immunology, Vol. 41, No. 7, 07.2011, p. 2086-2096.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Rapamycin-sensitive signals control TCR/CD28-driven Ifng, Il4 and Foxp3 transcription and promoter region methylation
AU - Tomasoni, Romana
AU - Basso, Veronica
AU - Pilipow, Karolina
AU - Sitia, Giovanni
AU - Saccani, Simona
AU - Agresti, Alessandra
AU - Mietton, Flore
AU - Natoli, Gioacchino
AU - Colombetti, Sara
AU - Mondino, Anna
PY - 2011/7
Y1 - 2011/7
N2 - 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.
AB - 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.
KW - Cell differentiation
KW - Cellular activation
KW - Gene expression
KW - T helper cells
UR - http://www.scopus.com/inward/record.url?scp=79959770321&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79959770321&partnerID=8YFLogxK
U2 - 10.1002/eji.201041130
DO - 10.1002/eji.201041130
M3 - Article
C2 - 21480212
AN - SCOPUS:79959770321
VL - 41
SP - 2086
EP - 2096
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 7
ER -