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Differential impact of mammalian target of rapamycin inhibition on CD4 +CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells
Open accessAbstract
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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“Beneficial downstream effects include Treg generation, suppressing CTL and T helper (TH) activation and at higher doses, B-cell proliferation and differentiation (69–71).”
From Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies (2021) · cites this paper as [71]
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Metadata
- Authors
- Zeiser, R., Leveson-Gower, D. B., Zambricki, E. A., Kambham, N., Beilhack, A., Loh, J., Hou, J.-Z., & Negrin, R. S.
- Affiliations
- University of Freiburg (DE)
- Stanford Medicine (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2008-01-01
- Volume
- 111
- Issue
- 1
- Pages
- 453-462
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2200823
- OpenAlex
- W1981298448
- Cited by
- 402
- References
- 52
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 9 · 2023: 17 · 2022: 9 · 2021: 21 · 2020: 17 · 2019: 21 · 2018: 23 · 2017: 18 · 2016: 31 · 2015: 24 · 2014: 33 · 2013: 27 · 2012: 32
- FWCI
- 8.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Krebshilfe
- National Institutes of Health (HL075462)
- National Heart, Lung, and Blood Institute (P01HL075462)
- National Cancer Institute (P50CA114747, R01 CA0800065, HL075462, R24 CA 92862, R24CA092862)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Transplantation › Renal Transplantation Outcomes and Treatments
- Keywords
- regulatory T cells, mTOR inhibition, rapamycin, acute graft-versus-host disease, conventional CD4+ T cells, STAT5 phosphorylation, PI3K/AKT/mTOR pathway, PTEN, Foxp3, interleukin-2, Treg therapy
- MeSH terms
- Animals, Graft vs Host Disease, Immunosuppressive Agents, Mice, Inbred BALB C, Mice, Inbred C57BL, Protein Kinases, CD4-Positive T-Lymphocytes, Hematopoietic Stem Cell Transplantation, Phosphatidylinositol 3-Kinases, Sirolimus, T-Lymphocytes, Regulatory, STAT5 Transcription Factor, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, Forkhead Transcription Factors, Interleukin-2 Receptor alpha Subunit, TOR Serine-Threonine Kinases
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