Mammalian Target of Rapamycin Complex 1 Orchestrates Invariant NKT Cell Differentiation and Effector Function

Zhang, Lianjun; Tschumi, Benjamin; Corgnac, Stéphanie; Rüegg, Markus A.; Hall, Michael N.; Mach, Jean‐Pierre; Romero, Pedro; Donda, Alena

doi:10.4049/jimmunol.1400769

Cited by 62 publications

(55 citation statements)

References 41 publications

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“…Of note, NKT thymocytes, unlike conventional T cells, undergo blasting and cell division during thymic development (1, 2). Consistent with this notion, loss of mTORC1 activity by deletion of Raptor has been shown in very recent studies to block development of iNKT cells at early stage and impair their functionality (16, 17), while permitting the normal development of conventional T cells. However, the role of mTOR in lineage diversification of iNKT cells is less clear (18).…”

Section: Introductionsupporting

confidence: 54%

Cutting Edge: Discrete Functions of mTOR Signaling in Invariant NKT Cell Development and NKT17 Fate Decision

Wei

Yang

Chi

2014

The Journal of Immunology

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Invariant natural killer T (iNKT) cells have been recently classified into NKT1, NKT2 and NKT17 lineages with distinct transcription factor and cytokine profiles, but mechanisms underlying such fate decisions remain elusive. Here, we report crucial roles of mTOR signaling especially mTORC2 in iNKT cell development and fate determination of NKT17 cells. Loss of Rictor, an obligatory component of mTORC2, decreased thymic and peripheral iNKT cells, associated with defective survival. Strikingly, Rictor deficiency selectively abolished the NKT17 lineage, as indicated by marked reduction of RORγt and IL-17 expression. Moreover, deletion of Pten upregulated mTORC2 activity and enhanced NKT17 generation, but concomitant loss of Rictor completely reversed the NKT17 dysregulation. In contrast, mTORC1 regulators Raptor and Rheb are dispensable for NKT17 differentiation, despite their importance in iNKT cell thymic development. Our findings establish pivotal and unique roles of mTORC2 signaling, which is reciprocally regulated by Rictor and Pten, in NKT17 lineage determination.

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Section: Introductionsupporting

confidence: 54%

Cutting Edge: Discrete Functions of mTOR Signaling in Invariant NKT Cell Development and NKT17 Fate Decision

Wei

Yang

Chi

2014

The Journal of Immunology

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“…We showed that autophagy deficiency led to hyperactivity of mTORC1 and mTORC2 in i NKT cells. The T cell specific deletion of Raptor, an essential component of mTORC1, also impaired the maturation of i NKT cells (70), suggesting the need for a balance, with either too much or too little mTORC1 inhibiting i NKT cell development.…”

Section: Discussionmentioning

confidence: 99%

Invariant NKT Cells Require Autophagy To Coordinate Proliferation and Survival Signals during Differentiation

Peng

Zhao

Miller

et al. 2015

The Journal of Immunology

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Autophagy regulates cell differentiation, proliferation and survival in multiple cell types, including cells of the immune system. Herein we examined the effects of a disruption of autophagy on the differentiation of invariant natural killer T cells (iNKT cells). Using mice with a T lymphocyte specific deletion of Atg5 or Atg7,two members of the macroautophagic pathway, we observed a profound decrease in the iNKT cell population. The deficit is cell-autonomous, and it acts predominantly to reduce the number of mature cells, as well as the function of peripheral iNKT cells. In the absence of autophagy, there is reduced progression of iNKT cells in the thymus through the cell cycle, as well as increased apoptosis of these cells. Importantly, the reduction in Th1-biased iNKT cells is most pronounced, leading to a selective reduction in iNKT cell derived IFNγ. Our findings highlight the unique metabolic and genetic requirements for the differentiation of iNKT cells.

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“…Indeed, ablation of mTORC1 signaling also causes a severe early defect in iNKT cell development (58,59). We speculate that iNKT cells undergo an early glycolytic shift driven by c-myc, but at the end of their expansion phase they have to be able to enter a quiescent, less metabolically active phase that relies on fatty acids, amino acids, and glucose as energy sources (60).…”

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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Mammalian Target of Rapamycin Complex 1 Orchestrates Invariant NKT Cell Differentiation and Effector Function

Cited by 62 publications

References 41 publications

Cutting Edge: Discrete Functions of mTOR Signaling in Invariant NKT Cell Development and NKT17 Fate Decision

Cutting Edge: Discrete Functions of mTOR Signaling in Invariant NKT Cell Development and NKT17 Fate Decision

Invariant NKT Cells Require Autophagy To Coordinate Proliferation and Survival Signals during Differentiation

Essential role for autophagy during invariant NKT cell development

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