Journal
BLOOD
Volume 111, Issue 1, Pages 453-462Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2007-06-094482
Keywords
-
Categories
Funding
- NATIONAL CANCER INSTITUTE [P50CA114747, R24CA092862] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL075462] Funding Source: NIH RePORTER
- NCI NIH HHS [R24 CA092862, P50 CA114747, R01-CA0800065, P50-CA114747, R24-CA92862] Funding Source: Medline
- NHLBI NIH HHS [P01 HL075462, P01-HL075462] Funding Source: Medline
Ask authors/readers for more resources
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 interieukin-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available