[PDF][PDF] The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment

GM Delgoffe, TP Kole, Y Zheng, PE Zarek… - Immunity, 2009 - cell.com
GM Delgoffe, TP Kole, Y Zheng, PE Zarek, KL Matthews, B Xiao, PF Worley, SC Kozma…
Immunity, 2009cell.com
Effector T cell differentiation requires the simultaneous integration of multiple, and
sometimes opposing, cytokine signals. We demonstrated mTOR's role in dictating the
outcome of T cell fate. mTOR-deficient T cells displayed normal activation and IL-2
production upon initial stimulation. However, such cells failed to differentiate into T helper 1
(Th1), Th2, or Th17 effector cells. The inability to differentiate was associated with decreased
STAT transcription factor activation and failure to upregulate lineage-specific transcription …
Summary
Effector T cell differentiation requires the simultaneous integration of multiple, and sometimes opposing, cytokine signals. We demonstrated mTOR's role in dictating the outcome of T cell fate. mTOR-deficient T cells displayed normal activation and IL-2 production upon initial stimulation. However, such cells failed to differentiate into T helper 1 (Th1), Th2, or Th17 effector cells. The inability to differentiate was associated with decreased STAT transcription factor activation and failure to upregulate lineage-specific transcription factors. Under normally activating conditions, T cells lacking mTOR differentiated into Foxp3+ regulatory T cells. This was associated with hyperactive Smad3 activation in the absence of exogenous TGF-β. Surprisingly, T cells selectively deficient in TORC1 do not divert to a regulatory T cell pathway, implicating both TORC1 and TORC2 in preventing the generation of regulatory T cells. Overall, our studies suggest that mTOR kinase signaling regulates decisions between effector and regulatory T cell lineage commitment.
cell.com