Differential effects of inhibitors of the PI3K/mTOR pathway on the expansion and functionality of regulatory T cells

Huijts, Charlotte M.; Santegoets, Saskia J.; Rey, Maria Quiles del; Haas, Richard R. de; Verheul, Henk M.W.; Gruijl, Tanja D. de; Vliet, Hans J. van der

doi:10.1016/j.clim.2016.05.005

Cited by 16 publications

(19 citation statements)

References 35 publications

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“…PI3K/AKT, p38 and JNK MAPKs were also involved in the HSP70-dependent activation of Tregs, while the MAPK ERK1/2 had a much lower impact on Tregs [30]. PI3K inhibition alone might exert antitumor effects without the detrimental selective expansion of Tregs associated with mTOR inhibition [27]. Similar to these findings, we observed the activation of PI3K/AKT and mTOR after stimulation with H/R-DEXs.…”

Section: Discussionsupporting

confidence: 81%

“…In addition, a recent study demonstrated that phosphatidylinositol 3-kinase (PI3K)/AKT, p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) were involved in HSP70-dependent activation of Tregs [30]. PI3K inhibition alone might offer antitumor efficacy without the detrimental selective expansion of Tregs associated with mTOR inhibition [27]. To verify the transport and function of HSP70, the co-culture of DEXs and naïve T cells was performed.…”

Section: Resultsmentioning

confidence: 99%

“…Where indicated, inhibitors were added to the cells 30 min prior to and during exosome treatment. Inhibitors were used at the concentrations according to Huijts et al [27]. Exosomes were pretreated with antibodies (anti-cmHsp70.1) for 30 min at a ratio of 1 μg antibody per 5 μg exosomes.…”

Section: Methodsmentioning

confidence: 99%

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Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion

Zheng¹,

Li²,

Wei³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The present study aimed to evaluate the effects as well as the underlying mechanisms of bone marrow-derived dendritic cells (BMDCs) and exosomes produced by BMDCs (DEXs) on hepatic ischemia-reperfusion (I/R) injury (IRI). Methods: Primary hepatocytes were isolated and used to mimic the liver IR microenvironment. BMDCs were induced and characterized both biochemically with a flow cytometer (FCM) and biophysically with a microscope. Then, we exposed BMDCs to the supernatants from primary hepatocytes and evaluated the maturation of BMDCs by FCM. BMDCs were systemically injected into mice before liver IR via the tail vein, and the therapeutic effects were evaluated. The serum levels of transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT), inflammatory cytokines, and histological changes were respectively examined by ELISA, RT-qPCR and microscopy. Furthermore, we isolated DEXs by ultracentrifugation, characterized DEXs by transmission electron microscopy (TEM) and nanosight tracking analysis (NTA) and western blotting (WB), and then we co-cultured BMDCs/DEXs and naïve T cells and performed FCM, ELISA and confocal imaging. Moreover, we injected DEXs into mice prior to liver IR via the tail vein and examined its therapeutic effects by microscopy and ELISA. Finally, inhibitors of HSP70 (cmHSP70.1), PI3K (BKM120) and mTOR (Rapamycin) were used to investigate the role of HSP70 and the PI3K/mTOR axis in the effects of DEXs on naïve T cells by WB and FCM. Results: Bone marrow cells were efficiently induced into dendritic cells (DCs) with typical DC characteristics. The supernatants from primary hepatocytes exposed to H/R upregulated DC maturation markers. After DC administration, liver IR injury was improved with histopathological scores and serum transaminases. Additionally, we found that the anti-inflammatory cytokines TGF-β, Foxp3 and interleukin (IL)-10 were upregulated and that IL-17 was downregulated. Furthermore, confocal imaging revealed that the uptake of H/R-DEXs by naïve T cells was greater than that of DEXs derived from the control or negative group of BMDCs, and this increase was correlated with a significantly greater degree of differentiation of Tregs and Th17 cells. Moreover, H/R-DEXs administration improved liver function in mice after IR. Finally, the inhibition of HSP70, PI3K and mTOR completely abolished the effect of DEXs on naïve T cells. Conclusion: These results demonstrated that BMDCs and DEXs could alleviate hepatic I/R injury via modulating the balance between Tregs and Th17 cells. DEXs transported HSP70 into naïve T cells and stimulated the PI3K/mTOR axis to modulate the balance between Tregs and Th17 cells and protect the liver from IR injury.

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Section: Discussionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

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Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion

Zheng¹,

Li²,

Wei³

et al. 2018

Cell Physiol Biochem

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“…The mTOR and dual PI3K/mTOR inhibitors have been shown to induce Tregs’ expansion and their immunosuppressive activity, thus correlating with a poor prognosis in cancer patients [123]. Encouragingly, Huijts and her group showed that the PI3K inhibition alone allows for the expansion of Tregs, but without affecting their overall suppressive activity [124]. …”

Section: Implications In Cancer Immunotherapymentioning

confidence: 99%

Role of mTOR Signaling in Tumor Microenvironment: An Overview

Cognetti

Bazzichetto

Falcone

et al. 2018

IJMS

112

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The mammalian target of rapamycin (mTOR) pathway regulates major processes by integrating a variety of exogenous cues, including diverse environmental inputs in the tumor microenvironment (TME). In recent years, it has been well recognized that cancer cells co-exist and co-evolve with their TME, which is often involved in drug resistance. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both the tumor immunity and angiogenesis. The activation of mTOR signaling is associated with these pro-oncogenic cellular processes, making mTOR a promising target for new combination therapies. This review highlights the role of mTOR signaling in the characterization and the activity of the TME’s elements and their implications in cancer immunotherapy.

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“…Rapamycin is a potent autophagy inducer in addition to its ability to block mTORC1 141. Recent studies show that mTORC1 regulates T-cell differentiation and its activation blocks FoxP3, a key transcription factor for Treg 139,142. Thus, rapamycin blockade of mTORC1 likely induces a variety of regulatory pathways in SEB-stimulated cells, including autophagic removal of damaged mitochondria, induction of functional Treg, downregulation of apoptosis, inflammatory cytokines, and T-cell proliferation.…”

Section: Repurposing Of Us Food and Drug Administration (Fda)-approvementioning

confidence: 99%

FDA-approved immunosuppressants targeting staphylococcal superantigens: mechanisms and insights

Krakauer¹

2017

ITT

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Immunostimulating staphylococcal enterotoxin B (SEB) and related superantigenic toxins cause diseases in human beings and laboratory animals by hyperactivating cells of the immune system. These protein toxins bind to the major histocompatibility complex class II (MHC II) molecules and specific Vβ regions of T-cell receptors (TCRs), resulting in the stimulation of both monocytes/macrophages and T lymphocytes. The bridging of TCR with MHC II molecules by superantigens triggers intracellular signaling cascades, resulting in excessive release of proinflammatory mediators and massive polyclonal T-cell proliferation. The early induction of tumor necrosis factor α, interleukin 1 (IL-1), interleukin 2 (IL-2), interferon gamma (IFNγ), and macrophage chemoattractant protein 1 promotes fever, inflammation, and multiple organ injury. The signal transduction pathways for staphylococcal superantigen-induced toxicity downstream from TCR/major histocompatibility complex (MHC) ligation and interaction of cell surface co-stimulatory molecules include the mitogen-activated protein kinase cascades and cytokine receptor signaling, activating nuclear factor κB (NFκB) and the phosphoinositide 3-kinase/mammalian target of rapamycin pathways. Knowledge of host regulation within these activated pathways and molecules initiated by SEB and other superantigens enables the selection of US Food and Drug Administration (FDA)-approved drugs to interrupt and prevent superantigen-induced shock in animal models. This review focuses on the use of FDA-approved immunosuppressants in targeting the signaling pathways induced by staphylococcal superantigens.

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Differential effects of inhibitors of the PI3K/mTOR pathway on the expansion and functionality of regulatory T cells

Cited by 16 publications

References 35 publications

Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion

Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion

Role of mTOR Signaling in Tumor Microenvironment: An Overview

FDA-approved immunosuppressants targeting staphylococcal superantigens: mechanisms and insights

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