A Role for Mammalian Target of Rapamycin in Regulating T Cell Activation versus Anergy

Zheng, Yan; Collins, Samuel; Lutz, Michael A.; Allen, Amy N.; Kole, Thomas P.; Zarek, Paul E.; Powell, Jonathan D.

doi:10.4049/jimmunol.178.4.2163

Cited by 248 publications

(254 citation statements)

References 37 publications

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“…We further examined the effects of TSC1 deficiency on mTOR signaling in T cells under activation and anergy conditions. WT naïve CD4 + T cells under anergy-inducing conditions exhibit decreased 4E-BP1 phosphorylation compared with those WT T cells under activating conditions, indicating that mTORC1 signaling is defective in anergic T cells, which was consistent with previous observations (15). However, TSC1-deficient naïve CD4 + T cells displayed elevated 4E-BP1 phosphorylation in both activating and anergy-inducing conditions (Fig.…”

Section: Contribution Of Enhanced Mtorc1 Signaling To the Resistance Ofsupporting

confidence: 82%

“…Engagement of the TCR activates both mTORC1 and mTORC2, which is dependent on the RasGRP1-Ras-Erk1/2 pathway and is inhibited by diacylglycerol kinases (11)(12)(13). Rapamycin treatment or genetic ablation of mTOR induces T-cell anergy and inhibits helper T-cell differentiation but promotes expansion of natural regulatory T cells (nTregs) and the generation of inducible Tregs (9,(14)(15)(16). Contrary to its positive role in promoting T-cell activation and effector T-cell function during primary immune responses, mTOR inhibits memory CD8 T-cell formation and function during viral infection (17,18).…”

Section: T-cell Activation | Signal Transductionmentioning

confidence: 99%

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Tumor suppressor TSC1 is critical for T-cell anergy

Xie

Lou

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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T-cell anergy is a state of T cells that is hyporesponsive to stimulation via the T-cell receptor and costimulatory molecules and is thought to be important for self-tolerance. How T-cell anergy is regulated is still poorly understood. We report here that tuberous sclerosis (TSC)1 is critical for T-cell anergy. Deficiency of TSC1 resulted in enhanced Tcell proliferation and cytokine production in the absence of cluster of differentiation (CD)28-mediated costimulation, accompanied by enhanced T-cell metabolism. Resistance of TSC1-deficient T cells to anergy is correlated with increased signaling through the mammalian target of rapamycin complex (mTORC)1 and can be reverted by treatment of these cells with mTORC1 inhibitor rapamycin. Expression of the inducible costimulator (ICOS) is increased in TSC1-deficient T cells, which can be inhibited by rapamycin. Simultaneous blockade of both CD28 and ICOS costimulation partially restored sensitivity of TSC1-deficient T cells to anergy induction. Together, our data indicate that TSC1 is crucial for T-cell anergy by inhibiting mTORC1 signaling through both ICOS-dependent and -independent mechanisms.T-cell activation | signal transduction C oordinated signals from the T-cell receptor (TCR), costimulatory receptors, and cytokine receptors ensure naïve T-cell activation and differentiation to proper effector T cells. T cells can be made anergic by stimulation through their TCR without a costimulatory signal, by stimulation with partial agonist peptides in the presence of costimulation, or by treatment with the Ca 2+ ionophore ionomycin (1-3). Anergic T cells do not respond to antigen restimulation even in the presence of appropriate costimulation. They are impaired in producing cytokines such as IFN-γ or IL-2, defective in proliferative response, and metabolically inert (4-7). T-cell anergy is thought to be important for preventing self-reactive T cells from full activation to trigger autoimmune diseases.The mammalian target of rapamycin (mTOR) integrates numerous environmental stimuli including growth factors, nutrients, and stress-activated signals to regulate cell metabolism, survival, growth, and proliferation (8). mTOR associates with multiple proteins and forms two distinct signaling complexes. mTOR complex (mTORC)1 contains raptor and phosphorylates ribosomal protein s6 kinase, 70-kd, 1 (S6K1) and eukaryotic translation initiation factor 4e-binding protein 1 (4E-BP1) to promote ribosomogenesis and protein translation. The rictor-containing mTORC2 phosphorylates both Akt at serine 473 residue to promote Akt activation and cell survival and PKCθ to promote T-helper (Th)2 differentiation (9, 10). Engagement of the TCR activates both mTORC1 and mTORC2, which is dependent on the RasGRP1-Ras-Erk1/2 pathway and is inhibited by diacylglycerol kinases (11-13). Rapamycin treatment or genetic ablation of mTOR induces T-cell anergy and inhibits helper T-cell differentiation but promotes expansion of natural regulatory T cells (nTregs) and the generation of inducible Tregs (9, 14-...

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Section: Contribution Of Enhanced Mtorc1 Signaling To the Resistance Ofsupporting

confidence: 82%

Section: T-cell Activation | Signal Transductionmentioning

confidence: 99%

Tumor suppressor TSC1 is critical for T-cell anergy

Xie

Lou

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…This increased activation and proliferation of DN T cells correlated with loss of their suppressive capacity. Previous studies linked Akt/ mTOR signaling to an anergic state of T cells by demonstrating that mTOR inhibition promotes T cell anergy (45)(46)(47). Of interest, our findings demonstrated that IL-7 downregulates expression of anergy-controlling factors FOXO, NFAT, p27kip1, EGR, and CBL in DN T cells, suggesting that IL-7/Akt/mTOR signaling abolishes an anergic-like state of the DN T cells.…”

Section: Discussionmentioning

confidence: 52%

IL-7 Abrogates the Immunosuppressive Function of Human Double-Negative T Cells by Activating Akt/mTOR Signaling

Allgäuer

Schreiner

Ferrazzi

et al. 2015

The Journal of Immunology

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Recently, a novel subset of TCRαβ+ CD4− CD8− double-negative (DN) T cells was described to suppress immune responses in both mice and humans. Moreover, in murine models, infusion and/or activation of DN T cells specifically suppressed alloreactive T cells and prevented the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. We demonstrated that human DN T cells, like their murine counterparts, are highly potent suppressor cells of both CD4+ and CD8+ T cell responses. After hematopoietic stem cell transplantation and other lymphopenic conditions, IL-7 plays an important role in the reconstitution, survival, and homeostasis of the T cell compartment. Because IL-7 was shown to interfere with T cell functionality, we asked whether IL-7 affects the functionality of human DN T cells. Intriguingly, IL-7 diminished the suppressive activity of DN T cells toward allogeneic CD4+ effector T cells. Of interest, our studies revealed that IL-7 activates the Akt/mechanistic target of rapamycin (mTOR) pathway in human DN T cells. Importantly, selective inhibition of the protein kinases Akt or mTOR reversed the IL-7 effect, thereby restoring the functionality of DN T cells, whereas inhibition of other central T cell signaling pathways did not. Further analyses suggest that the IL-7/Akt/mTOR signaling cascade downregulates anergy-associated genes and upregulates activation- and proliferation-associated factors that may be crucial for DN T cell functionality. These findings indicate that IL-7 and Akt/mTOR signaling are critical factors for the suppressive capacity of DN T cells. Targeting of these pathways by pharmacological agents may restore and/or enhance DN T cell functionality in graft-versus-host disease.

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“…Cellular composition of plaque might not only influence plaque growth but also its stability. Previous reports in experimental and human atherosclerotic lesions suggest that increased macrophage activities mostly associated with inflammatory processes, extracellular lipid accumulation, or decreased SMC density might be the pathogenic basis for plaque instability 18,19) . Macrophages in the vascular wall can be selectively cleared via the induction of autophages by m-TOR inhibition 20) .…”

Section: Discussionmentioning

confidence: 99%

Origin of Restenosis after Drug-Eluting Stent Implantation in Hyperglycemia is Inflammatory Cells and Thrombus

Kwon

Kim

Cho

et al. 2011

JAT

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Aims:The cellular and molecular mechanisms and safety after drug-eluting stent (DES) implantation in diabetic patients are still poorly understood; therefore, in this study, we evaluated the pathologic responses of the sirolimus-eluting stent (SES) or paclitaxel-eluting stent (PES) in a type diabetes mellitus (DM) rat model. Methods:The type DM rat model was manipulated by intra-peritoneal streptozotocin injection. Two weeks later, DES was implanted in the aorta of rats with hyperglycemia or not as a control. Four weeks after DES implantation, the stented aorta was isolated and histomorphometric analysis was performed. Results: On histomorphometric analysis, increased thrombus, inflammatory cell infiltration, and neointimal hyperplasia (NIH) without change of the smooth muscle cell number after DES implantation were observed in DM rats compared with non-DM (NDM) rats. Furthermore, delayed coverage of mature endothelial cells defined as a von Willebrand factor expression and increased immature endothelial cells as a c-kit expression after DES implantation were observed in DM rats compared with NDM rats. Increased fibrin deposition and decreased hyaluronic acid accumulation at NIH after DES implantation were also observed in DM rats compared with NDM rats. Conclusions: In conclusion, the main mechanism of restenosis after DES implantation under hyperglycemic conditions was initial thrombus with changes of the extracellular matrix rather than SMC proliferation. These results provided a therapeutic clue for the selection of DES and application of combination therapy using anti-thrombotic and anti-inflammatory drugs in diabetic patients. J Atheroscler Thromb, 2011; 18:604-615.

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A Role for Mammalian Target of Rapamycin in Regulating T Cell Activation versus Anergy

Cited by 248 publications

References 37 publications

Tumor suppressor TSC1 is critical for T-cell anergy

Tumor suppressor TSC1 is critical for T-cell anergy

IL-7 Abrogates the Immunosuppressive Function of Human Double-Negative T Cells by Activating Akt/mTOR Signaling

Origin of Restenosis after Drug-Eluting Stent Implantation in Hyperglycemia is Inflammatory Cells and Thrombus

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