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

• DOI: 10.1002/eji.201041130
• Publication Date: 2011-04-08T07:58:34Z
• Authors: Romana Tomasoni; Veronica Basso; Karolina Pilipow; Giovanni Sitia; Simona Saccani; Alessandra Agresti; Flore Mietton; Gioacchino Natoli; Sara Colombetti; Anna Mondino
• Keywords: Transcription

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