Anergic T Cells Are Metabolically Anergic

Zheng, Yan; Delgoffe, Greg M.; Meyer, Christian F.; Chan, Waipan; Powell, Jonathan D.

doi:10.4049/jimmunol.0803510

Cited by 246 publications

(265 citation statements)

References 35 publications

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“…For T cell activation, anti-CD28 (37.51), anti-CD3 (2C11), and interleukin 2 (IL-2) were purchased from BD Biosciences or produced as described (23). Antibodies to P-S6 (Ser 240/244 ), S6, P-4EBP-1 (Thr 37/46 ), 4EBP-1, ␤-tubulin, and pan-actin were purchased from Cell Signaling Technologies (Danvers, MA).…”

Section: Methodsmentioning

confidence: 99%

“…Sinclair et al (22) showed that the System L transporter, Slc7a5, is a key factor in T cell metabolic reprogramming that directs Leu transport and controls mTORC1 activity (22). Moreover, the Leu antagonist N-acetyl-leucine amide (NALA) inhibits mTORC1 activity and T cell function (23). Similarity, essential amino acid depletion inhibits mTOR and promotes infectious tolerance via generation of regulatory T cells (21).…”

mentioning

confidence: 99%

“…There is accumulating evidence that Leu and Leu cellular import are involved in T cell activation (21)(22)(23). Sinclair et al (22) showed that the System L transporter, Slc7a5, is a key factor in T cell metabolic reprogramming that directs Leu transport and controls mTORC1 activity (22).…”

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confidence: 99%

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Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells

Ananieva

Patel

Drake

et al. 2014

Journal of Biological Chemistry

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Background: Cytosolic branched chain aminotransferase (BCATc) initiates Leu catabolism. In T cells, Leu activates mTORC1, the role of BCATc is unknown. Results: BCATc stimulates Leu transamination, whereas loss of BCATc expression increases Leu concentrations, mTORC1 signaling, and glycolysis in T cells. Conclusion: BCATc is a novel immunosuppressive enzyme controlling Leu supply for mTORC1 in T cells. Significance: A new link is revealed between amino acid metabolism and the immune response.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells

Ananieva

Patel

Drake

et al. 2014

Journal of Biological Chemistry

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“…During the transition from the naïve resting state to an activated state, T-cell metabolism is substantially increased, including increased uptake of nutrients, accelerated glycolysis, and massive protein and DNA synthesis. In contrast, anergic T cells are thought to be metabolically anergic (6). Because mTOR is a central regulator of metabolism and is regulated by TSC1, we investigated whether TSC1 controls T-cell metabolism.…”

Section: Contribution Of Enhanced Mtorc1 Signaling To the Resistance Ofmentioning

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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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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“…43 Interestingly, enhanced AMPK activation, which we observed in PP4-deficient T cells, has also been implicated in the induction of anergy. 43,44 The results in this report then lead us to speculate that PP4 may serve as a novel mediator for the anergy avoidance signal, 4,5 so that T cells receiving proper TCR and co-stimulatory signals may proliferate and differentiate normally. In this regard, 2 observations distinguish our CD4cre:PP4 f/f mice from the current paradigm of anergy induction 43 : first, exogenous IL-2 fails to rescue PP4-deficient T cells from their unresponsive state (Fig.…”

Section: Discussionmentioning

confidence: 99%

T cell proliferation and adaptive immune responses are critically regulated by protein phosphatase 4

et al. 2016

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The clonal expansion of activated T cells is pivotal for the induction of protective immunity. Protein phosphatase 4 (PP4) is a ubiquitously expressed serine/threonine phosphatase with reported functions in thymocyte development and DNA damage responses. However, the role of PP4 in T cell immunity has not been thoroughly investigated. In this report, our data showed that T cell-specific ablation of PP4 resulted in defective adaptive immunity, impaired T cell homeostatic expansion, and inefficient T cell proliferation. This hypo-proliferation was associated with a partial G1-S cell cycle arrest, enhanced transcriptions of CDK inhibitors and elevated activation of AMPK. In addition, resveratrol, a known AMPK activator, induced similar G1-S arrests, while lentivirally-transduced WT or constitutively-active AMPKa1 retarded the proliferation of WT T cells. Further investigations showed that PP4 co-immunoprecipitated with AMPKa1, and the over-expression of PP4 inhibited AMPK phosphorylation, thereby implicating PP4 for the negative regulation of AMPK. In summary, our results indicate that PP4 is an essential modulator for T cell proliferation and immune responses; they further suggest a potential link between PP4 functions, AMPK activation and G1-S arrest in activated T cells.

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Anergic T Cells Are Metabolically Anergic

Cited by 246 publications

References 35 publications

Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells

Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells

Tumor suppressor TSC1 is critical for T-cell anergy

T cell proliferation and adaptive immune responses are critically regulated by protein phosphatase 4

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