PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8<sup>+</sup>T cells

Finlay, David K.; Rosenzweig, Ella; Sinclair, Linda V.; Feijoo-Carnero, Carmen; Hukelmann, Jens; Rolf, Julia; Panteleyev, Andrey; Okkenhaug, Klaus; Cantrell, Doreen A.

doi:10.1083/jcb1996oia8

Cited by 94 publications

(158 citation statements)

References 22 publications

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“…Hyperactivated mTOR is observed in many types of cancers and autoimmune disease (55,56). Although the PI3K/AKT pathway is considered a canonical upstream regulator of mTOR, the activation of mTOR also can occur through AKT-independent mechanisms (57)(58)(59). In this study, our results suggest that FTY720 negatively regulates MDSC functions in an mTOR-dependent, but largely AKT-independent, manner (Fig.…”

Section: Ly6gsupporting

confidence: 59%

Targeting S1P1 Receptor Protects against Murine Immunological Hepatic Injury through Myeloid-Derived Suppressor Cells

Liu

Wang

et al. 2014

The Journal of Immunology

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Although FTY720 may alter migration and homing of lymphocytes via sphingosine-1-phosphate (S1P) receptors, our recent studies indicated that FTY720 directly controls the differentiation of Th1 cells to regulatory T cells (Tregs) by targeting S1P1. However, the pharmacological function of FTY720 in immunological hepatic injury remains unknown. In this study, the role and regulatory signaling pathway of S1P receptor were investigated using a pharmacological approach in immune-mediated hepatic injury (IMH). In the context of IMH, FTY720 significantly ameliorated mortality and hepatic pathology. In FTY720-treated mice, recruited CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) mediate protection against IMH and are functional suppressive immune modulators that result in fewer IFN-γ–producing Th1 cells and more Foxp3+ Tregs. In agreement, FTY720-treated MDSCs promote the reciprocal differentiation between Th1 cells and Tregs in vitro and in vivo. Mechanistically, FTY720 treatment induced inducible NO synthase expression and NO production in MDSCs. Pharmacologic inhibition of inducible NO synthase completely eliminates MDSC suppressive function and eradicates their inducible effects on T cell differentiation. Finally, the mTOR inhibitor, rapamycin, photocopies the effects of FTY720 on MDSCs, implicating mTOR as a downstream effector of S1P1 signaling. This study identifies MDSCs as an essential component that provides protection against IMH following FTY720 or rapamycin treatment, validating the S1P1–mTOR signaling axis as a potential therapeutic target in hepatic injury.

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Section: Ly6gsupporting

confidence: 59%

Targeting S1P1 Receptor Protects against Murine Immunological Hepatic Injury through Myeloid-Derived Suppressor Cells

Liu

Wang

et al. 2014

The Journal of Immunology

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“…Our observation that mTORC1 activity is reduced rather than abolished and that it is normal during the first 8 h of TCR stimulation suggested that perturbed mTORC1 signaling may not be the main cause for the profound proliferation defect in T cells lacking dynamin 2. This possibility is also supported by the observation that, in contrast to dynamin 2, mTOR is dispensable for the clonal expansion of T cells (21). We therefore explored other pathways that regulate cell growth in T cells.…”

Section: Reprogramming Of T-cell Metabolism Through C-myc Is Dependenmentioning

confidence: 69%

Dynamin 2-dependent endocytosis sustains T-cell receptor signaling and drives metabolic reprogramming in T lymphocytes

Willinger¹,

Staron²,

Ferguson³

et al. 2015

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

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Prolonged T-cell receptor (TCR) signaling is required for the proliferation of T lymphocytes. Ligation of the TCR activates signaling, but also causes internalization of the TCR from the cell surface. How TCR signaling is sustained for many hours despite lower surface expression is unknown. Using genetic inhibition of endocytosis, we show here that TCR internalization promotes continued TCR signaling and T-lymphocyte proliferation. T-cell–specific deletion of dynamin 2, an essential component of endocytosis, resulted in reduced TCR signaling strength, impaired homeostatic proliferation, and the inability to undergo clonal expansion in vivo. Blocking endocytosis resulted in a failure to maintain mammalian target of rapamycin (mTOR) activity and to stably induce the transcription factor myelocytomatosis oncogene (c-Myc), which led to metabolic stress and a defect in cell growth. Our results support the concept that the TCR can continue to signal after it is internalized from the cell surface, thereby enabling sustained signaling and cell proliferation.

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“…+ T cells HIF1-α can sustain the glycolytic response downstream of mTOR (56,57), it remains to be established whether, in addition to c-myc, it also plays an important role in regulating iNKT cell development, perhaps by sustaining the glycolytic switch during population expansion.…”

Section: Discussionmentioning

confidence: 99%

Essential role for autophagy during invariant NKT cell development

Salio

Puleston

Mathan

et al. 2014

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

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Autophagy is an evolutionarily conserved cellular homeostatic pathway essential for development, immunity, and cell death. Although autophagy modulates MHC antigen presentation, it remains unclear whether autophagy defects impact on CD1d lipid loading and presentation to invariant natural killer T (iNKT) cells and on iNKT cell differentiation in the thymus. Furthermore, it remains unclear whether iNKT and conventional T cells have similar autophagy requirements for differentiation, survival, and/or activation. We report that, in mice with a conditional deletion of the essential autophagy gene Atg7 in the T-cell compartment (CD4 Cre-Atg7), thymic iNKT cell development-unlike conventional T-cell development-is blocked at an early stage and mature iNKT cells are absent in peripheral lymphoid organs. The defect is not due to altered loading of intracellular iNKT cell agonists; rather, it is T-cell-intrinsic, resulting in enhanced susceptibility of iNKT cells to apoptosis. We show that autophagy increases during iNKT cell thymic differentiation and that it developmentally regulates mitochondrial content through mitophagy in the thymus of mice and humans. Autophagy defects result in the intracellular accumulation of mitochondrial superoxide species and subsequent apoptotic cell death. Although autophagy-deficient conventional T cells develop normally, they show impaired peripheral survival, particularly memory CD8 + T cells. Because iNKT cells, unlike conventional T cells, differentiate into memory cells while in the thymus, our results highlight a unique autophagy-dependent metabolic regulation of adaptive and innate T cells, which is required for transition to a quiescent state after population expansion.utophagy is an evolutionarily conserved catabolic process that, by facilitating the breakdown and recycling of damaged organelles and long-lived proteins, is essential to maintaining cellular homeostasis (1). The autophagy pathway is highly regulated during development and also by environmental factors such as nutrient availability/starvation, hypoxia, and reactive oxygen species (ROS). The process is controlled by a number of autophagy-related genes (Atg) and starts with the formation of a double-membraned vesicle (the autophagosome) engulfing the cytoplasmic components to be delivered to the lysosome for degradation. Formation of the autophagosome requires the concerted action of two ubiquitin-like conjugation systems in which Atg12 is covalently linked to Atg5 and Atg8 is conjugated to phosphatidylethanolamine (2, 3). Atg7 is a necessary catalyst in both conjugation systems and is therefore essential for autophagy (3).Due to its important role in cellular homeostasis, dysregulation of autophagy has been implicated in several pathological processes, including neurodegeneration, autoimmunity, cancer, and infection (4). Furthermore, autophagy plays an important role during immune responses by regulating pathogen handling and antigen presentation (5, 6). It is well established that different populations of αβ T lymph...

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PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8⁺T cells

Cited by 94 publications

References 22 publications

Targeting S1P1 Receptor Protects against Murine Immunological Hepatic Injury through Myeloid-Derived Suppressor Cells

Targeting S1P1 Receptor Protects against Murine Immunological Hepatic Injury through Myeloid-Derived Suppressor Cells

Dynamin 2-dependent endocytosis sustains T-cell receptor signaling and drives metabolic reprogramming in T lymphocytes

Essential role for autophagy during invariant NKT cell development

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PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+T cells

Cited by 94 publications

References 22 publications

Targeting S1P1 Receptor Protects against Murine Immunological Hepatic Injury through Myeloid-Derived Suppressor Cells

Targeting S1P1 Receptor Protects against Murine Immunological Hepatic Injury through Myeloid-Derived Suppressor Cells

Dynamin 2-dependent endocytosis sustains T-cell receptor signaling and drives metabolic reprogramming in T lymphocytes

Essential role for autophagy during invariant NKT cell development

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PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8⁺T cells