Beschreibung:
<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>Ifng</jats:italic>, <jats:italic>Il4</jats:italic> and <jats:italic>Foxp3</jats:italic>, 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, <jats:italic>Ifng</jats:italic>, <jats:italic>Il4</jats:italic> and <jats:italic>Foxp3</jats:italic> 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 <jats:italic>Ifng</jats:italic> and <jats:italic>Il4</jats:italic> promoter regions. In contrast, RAPA prevented activation‐dependent DNA methylation of the <jats:italic>Foxp3</jats:italic> promoter favoring <jats:italic>Foxp3</jats:italic> expression. As a result, RAPA‐cultured cells lacked immediate effector functions and instead were enriched for IL‐2<jats:sup>+</jats:sup> 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.</jats:p>