The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function

Yang, Kai; Neale, Geoffrey; Green, Douglas R.; He, Wei; Chi, Hongbo

doi:10.1038/ni.2068

Cited by 241 publications

(344 citation statements)

References 49 publications

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“…Activation of mTORC1 and mTORC2 upon TCR stimulation depends on PI3K-AKT, as well as Ras guanyl releasing protein 1 (RasGRP1)-Ras-Erk1/2 pathways (10). Additional studies, including ours, have demonstrated that mTOR and its tight regulation by the tumor suppressor TSC1 play crucial roles in T-cell differentiation, survival, quiescence, and migration, as well as other immune cell development and function (11)(12)(13)(14)(15)(16)(17). However, the role of mTOR in iNKT cells is unclear.…”

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confidence: 89%

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Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function

Shin¹,

Wang

Deng

et al. 2014

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

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The mechanisms that control invariant natural killer T (iNKT)-cell development and function are still poorly understood. The mechanistic or mammalian target of rapamycin (mTOR) integrates various environmental signals/cues to regulate cell growth, proliferation, metabolism, and survival. We report here that ablation of mTOR complex 1 (mTORC1) signaling by conditionally deleting Raptor causes severe defects in iNKT-cell development at early stages, leading to drastic reductions in iNKT-cell numbers in the thymus and periphery. In addition, loss of Raptor impairs iNKT-cell proliferation and production of cytokines upon α-galactosylceramide stimulation in vitro and in vivo, and inhibits liver inflammation in an iNKT cell-mediated hepatitis model. Furthermore, Raptor deficiency and rapamycin treatment lead to aberrant intracellular localization and functional impairment of promyelocytic leukemia zinc-finger, a transcription factor critical for iNKT-cell development and effector programs. Our findings define an essential role of mTORC1 to direct iNKT-cell lineage development and effector function.

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confidence: 89%

“…PLZF may function as a negative feedback mechanism to dampen mTORC1 activation. Hyperactivation of mTORC1 poses detrimental effects in other immune cells (12)(13)(14)(15)(16)(17). Fine-tuning of mTORC1 and PLZF activities may be crucial for the proper development and function of iNKT cells and many other cell types.…”

Section: Significancementioning

confidence: 99%

Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function

Shin¹,

Wang

Deng

et al. 2014

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

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“…Tuberous sclerosis 1 (Tsc1), a negative regulator of mTORC1 signaling (26), has been implicated in T-cell homeostasis and anergy (27)(28)(29)(30). We and others have demonstrated that deletion of Tsc1 in naïve T cells disrupts their quiescence and survival and dampens T-cell-mediated primary responses to bacterial infection (27)(28)(29).…”

Section: Significancementioning

confidence: 99%

“…We and others have demonstrated that deletion of Tsc1 in naïve T cells disrupts their quiescence and survival and dampens T-cell-mediated primary responses to bacterial infection (27)(28)(29). To circumvent the crucial requirement of Tsc1 in naïve T-cell homeostasis, we developed a mouse model to specifically delete Tsc1 in antigen-experienced CD8 + T cells.…”

Section: Significancementioning

confidence: 99%

Tsc1 promotes the differentiation of memory CD8 ⁺ T cells via orchestrating the transcriptional and metabolic programs

Shrestha

Yang²,

Wei³

et al. 2014

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

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Significance Enhancing the generation and function of memory T cells represents a crucial strategy to improve protective immunity against pathogens and tumors. The signaling pathway via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells, but the upstream regulators or downstream mechanisms remain unclear. In this study, we provide insight into the mechanistic basis that controls mTOR signaling and memory T-cell responses. The deficiency of tuberous sclerosis 1 (Tsc1) in antigen-experienced T cells impairs the differentiation of memory T-cell precursors and the formation of memory T cells, associated with excessive mTOR activity and dysregulated cell metabolism. Our study establishes a molecular mechanism that links mTOR signaling and cell metabolism for memory T-cell development.

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“…TSC1 and TSC2 proteins form a heterodimeric complex that acts as a functional unit and are closely involved in a wide range of cellular functions [10][11][12][13] . TSC1 enhances TSC2 activity by stabilizing TSC2 (ref.…”

mentioning

confidence: 99%

TSC1 controls macrophage polarization to prevent inflammatory disease

et al. 2014

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Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses, but the mechanisms that regulate the macrophage polarization are poorly defined. Here we show that tuberous sclerosis complex 1 (TSC1) is a critical regulator of M1 and M2 phenotypes of macrophages. Mice with myeloid-specific deletion of TSC1 exhibit enhanced M1 response and spontaneously develop M1-related inflammatory disorders. However, TSC1-deficient mice are highly resistant to M2-polarized allergic asthma. Inhibition of the mammalian target of rapamycin (mTOR) fails to reverse the hypersensitive M1 response of TSC1-deficient macrophages, but efficiently rescues the defective M2 polarization. Deletion of mTOR also fails to reverse the enhanced inflammatory response of TSC1-deficient macrophages. Molecular studies indicate that TSC1 inhibits M1 polarization by suppressing the Ras GTPase-Raf1-MEK-ERK pathway in mTOR-independent manner, whereas TSC1 promotes M2 properties by mTOR-dependent CCAAT/enhancer-binding protein-b pathways. Overall, these findings define a key role for TSC1 in orchestrating macrophage polarization via mTOR-dependent and independent pathways.

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The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function

Cited by 241 publications

References 49 publications

Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function

Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function

Tsc1 promotes the differentiation of memory CD8 ⁺ T cells via orchestrating the transcriptional and metabolic programs

TSC1 controls macrophage polarization to prevent inflammatory disease

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The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function

Cited by 241 publications

References 49 publications

Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function

Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function

Tsc1 promotes the differentiation of memory CD8 + T cells via orchestrating the transcriptional and metabolic programs

TSC1 controls macrophage polarization to prevent inflammatory disease

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Product

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Tsc1 promotes the differentiation of memory CD8 ⁺ T cells via orchestrating the transcriptional and metabolic programs