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Blood, 1 January 2008, Vol. 111, No. 1, pp. 453-462.
Prepublished online as a Blood First Edition Paper on October 29, 2007; DOI 10.1182/blood-2007-06-094482.
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TRANSPLANTATION
Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells
Robert Zeiser1,2,
Dennis B. Leveson-Gower1,
Elizabeth A. Zambricki1,
Neeraja Kambham3,
Andreas Beilhack1,
John Loh1,
Jing-Zhou Hou1, and
Robert S. Negrin1
1 Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA;
2 Division of Hematology and Oncology, Department of Medicine, Albert Ludwigs University Freiburg, Freiburg, Germany; and
3 Department of Pathology, Stanford University School of Medicine, Stanford, CA
Based on their ability to control T-cell homeostasis, Foxp3+CD4+CD25+ regulatory T cells (Tregs) are being considered for treatment of autoimmune disorders and acute graft-versus-host disease (aGVHD). When combining Tregs with the immunosuppressant rapamycin (RAPA), we observed reduced alloreactive conventional T-cell (Tconv) expansion and aGVHD lethality compared with each treatment alone. This synergistic in vivo protection was paralleled by intact expansion of polyclonal Tregs with conserved high FoxP3 expression. In contrast to Tconv, activation of Tregs with alloantigen and interleukin-2 preferentially led to signal transducer and activator of transcription 5 (STAT5) phosphorylation and not phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activity. Expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a negative regulator of the PI3K/Akt/mTOR pathway, remained high in Tregs but not Tconv during stimulation. Conversely, targeted deletion of PTEN increased susceptibility of Tregs to mTOR inhibition by RAPA. Differential impact of RAPA as a result of reduced usage of the mTOR pathway in Tregs compared with conventional T cells explains the synergistic effect of RAPA and Tregs in aGVHD protection, which has important implications for clinical trials using Tregs.
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