Lactate exposure shapes the metabolic and transcriptomic profile of CD8+ T cells

IntroductionCD8+ T cells infiltrate virtually every tissue to find and destroy infected or mutated cells. They often traverse varying oxygen levels and nutrient-deprived microenvironments. High glycolytic activity in local tissues can result in significant exposure of cytotoxic T cells to the lactate metabolite. Lactate has been known to act as an immunosuppressor, at least in part due to its association with tissue acidosis.MethodsTo dissect the role of the lactate anion, independently of pH, we performed phenotypical and metabolic assays, high-throughput RNA sequencing, and mass spectrometry, on primary cultures of murine or human CD8+ T cells exposed to high doses of pH-neutral sodium lactate.ResultsThe lactate anion is well tolerated by CD8+ T cells in pH neutral conditions. We describe how lactate is taken up by activated CD8+ T cells and can displace glucose as a carbon source. Activation in the presence of sodium lactate significantly alters the CD8+ T cell transcriptome, including the expression key effector differentiation markers such as granzyme B and interferon-gamma.DiscussionOur studies reveal novel metabolic features of lactate utilization by activated CD8+ T cells, and highlight the importance of lactate in shaping the differentiation and activity of cytotoxic T cells

Cytotoxic T-cells mediate exercise-induced reductions in tumor growth

Funder: Vetenskapsrådet; FundRef: http://dx.doi.org/10.13039/501100004359Funder: Cancerfonden; FundRef: http://dx.doi.org/10.13039/501100002794Funder: Barncancerfonden; FundRef: http://dx.doi.org/10.13039/501100006313Funder: Svenska Läkaresällskapet; FundRef: http://dx.doi.org/10.13039/501100007687Funder: Cancer Research UK; FundRef: http://dx.doi.org/10.13039/501100000289Funder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265Exercise has a wide range of systemic effects. In animal models, repeated exertion reduces malignant tumor progression, and clinically, exercise can improve outcome for cancer patients. The etiology of the effects of exercise on tumor progression are unclear, as are the cellular actors involved. We show here that in mice, exercise-induced reduction in tumor growth is dependent on CD8+ T cells, and that metabolites produced in skeletal muscle and excreted into plasma at high levels during exertion in both mice and humans enhance the effector profile of CD8+ T-cells. We found that activated murine CD8+ T cells alter their central carbon metabolism in response to exertion in vivo, and that immune cells from trained mice are more potent antitumor effector cells when transferred into tumor-bearing untrained animals. These data demonstrate that CD8+ T cells are metabolically altered by exercise in a manner that acts to improve their antitumoral efficacy

Channel estimation method with improved performance for the UMTS-TDD mode

Channel estimation is an essential building block for UTRA-TDD high performance receivers. Once the performance of the channel estimator algorithm proposed by 3GPP is highly dependent on the time spreading between consecutive multi-path components, a Successive Multi-path channel Estimation Technique (SMET) that improves the time resolution is proposed in this paper. A SMET based maximum likelihood approach for vectorial channel estimation, to include the estimation of the direction-of-arrival, is also proposed. This algorithm solves efficiently the complex problem of DOA estimation of multiple users in a multi path propagation environment even when the number of required DOA's exceeds the number of antenna array elements. Another property of the proposed algorithm is its ability to resolve signals from different users arriving from the same direction. This is due to processing in both time and space dimensions. The performance of these algorithms is assessed by resorting to simulations in multi-path environments using the UMTS-TDD specifications, and also by comparing the rms estimation errors against the Crámer-Rao Bound. The effect of imperfect channel estimation on the performance of RAKE and Hard-Decision Parallel Interference Canceller receivers is also analysed. The results show that a good performance can be achieved with SMET, from low to high values of Eb/n0

Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth

A systems approach using 13C metabolic flux analysis (MFA), non-targeted tracer fate detection (NTFD), and transcriptional profiling was applied to investigate the role of oncogenic K-Ras in metabolic transformation.K-Ras transformed cells exhibit an increased glycolytic rate and lower flux through the oxidative tricarboxylic acid (TCA) cycle.K-Ras transformed cells show a relative increase in glutamine anaplerosis and reductive TCA metabolism.Transcriptional changes driven by oncogenic K-Ras suggest control nodes associated with the metabolic reprogramming of cancer cells

I rörelse / On the Move : Acsis Conference 2013, Norrköping 11-13 June

We are proud to welcome you to the conference On the Move. It is arranged by the Advanced Cultural Studies Institute of Sweden (ACSIS) which is a national center for interdisciplinary and international networking in cultural research. This is the fifth biannual ACSIS conference. All the conferences have had different themes connected to various aspects of cultural research. On the Move explores the “mobility turn,” starting within the social sciences, and it explores the evolution in media studies, cultural studies, sociology, ethnology, anthropology, tourism studies, literature studies and several other areas of cultural research. Papers explore movement and/or immobilization across a broad spectrum and within many contexts, from the micro-movements of streptococci to the mobile, or not so mobile, lives of artists and artistic productions, cosmopolitans, refugees and tourists. They address social, cultural and political movements as well as practices embodied in sports, dance and everyday life. In addition to the exploration of the spatial mobility of humans, organisms and objects, the circulation across time and space of representations and the vehicles for movement – topics at the heart of the mobility turn – this conference also presents plenary panels and sessions dealing with the transformation of cultural and social norms. The speakers will discuss and debate the changing values with regard to gender and normativity; motion and emotion; the prerequisites and practices of critical research and teaching; the historiography of Europe; and cultural production and consumption. In the spirit of internationalization we have decided to alternate between two English, whereas all session slots have English as well as Swedish alternatives. This mixture of languages is a reality for many non-English natives and an inevitable aspect of doing cultural research – on the move – today. The conference is supported by Linköping University’s Faculty of Arts and Science, the Swedish universities which co-fund ACSIS, the Bank of Sweden Tercentenary Foundation and the city of Norrköping. We are also enormously grateful for and impressed by the non-salaried efforts from all invited speakers, panelists, moderators, session organizers and paper presenters. We invite you to discover the conference’s rich and varied content. Finally, we wish to stress that conferences are not only work; they are also a great opportunity to meet old friends and make new ones. In addition to the discussions at the sessions, there will be plenty of time to socialize at the reception hosted by the city of Norrköping on Tuesday evening and the conference dinner on Wednesday night. Bodil Axelsson, Director of ACSIS Orvar Löfgren, Chair of the ACSIS board Johanna Dahlin, ACSIS coordinator and conference organizerGrafisk form: Tove AnderssonOmslagsfoto: David Torell</p

Nutrient Deprivation Elicits a Transcriptional and Translational Inflammatory Response Coupled to Decreased Protein Synthesis

Summary: Nutrient deprivation inhibits mRNA translation through mTOR and eIF2α signaling, but it is unclear how the translational program is controlled to reflect the degree of a metabolic stress. In a model of breast cellular transformation, various forms of nutrient deprivation differentially affect the rate of protein synthesis and its recovery over time. Genome-wide translational profiling of glutamine-deprived cells reveals a rapid upregulation of mRNAs containing uORFs and downregulation of ribosomal protein mRNAs, which are followed by selective translation of cytokine and inflammatory mRNAs. Transcription and translation of inflammatory and cytokine genes are stimulated in response to diverse metabolic stresses and depend on eIF2α phosphorylation, with the extent of stimulation correlating with the decrease in global protein synthesis. In accord with the inflammatory stimulus, glutamine deprivation stimulates the migration of transformed cells. Thus, pro-inflammatory gene expression is coupled to metabolic stress, and this can affect cancer cell behavior upon nutrient limitation. : Deprivation of some nutrients may impose more constraints on mRNA translation than others. Gameiro and Struhl describe a relationship between translational repression and pro-inflammatory gene expression in response to various metabolic stresses. The pro-inflammatory transcriptional and translational response is not triggered by mTOR inhibition, per se, and requires eIF2α phosphorylation. Keywords: inflammation, glutamine, metabolism, translational control, protein synthesis, cancer, mTOR, eIF2

In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation

PMCID: PMC4003458; NIHMSID: NIHMS449661.-- et al.Hypoxic and VHL-deficient cells use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate. To gain insights into the role of HIF and the molecular mechanisms underlying RC, we took advantage of a panel of disease-associated VHL mutants and showed that HIF expression is necessary and sufficient for the induction of RC in human renal cell carcinoma (RCC) cells. HIF expression drastically reduced intracellular citrate levels. Feeding VHL-deficient RCC cells with acetate or citrate or knocking down PDK-1 and ACLY restored citrate levels and suppressed RC. These data suggest that HIF-induced low intracellular citrate levels promote the reductive flux by mass action to maintain lipogenesis. Using [ 1-13C]glutamine, we demonstrated in vivo RC activity in VHL-deficient tumors growing as xenografts in mice. Lastly, HIF rendered VHL-deficient cells sensitive to glutamine deprivation in vitro, and systemic administration of glutaminase inhibitors suppressed the growth of RCC cells as mice xenografts. © 2013 Elsevier Inc.This work was supported by NIH R01 CA122591, the MGH Proton Beam Federal Share Project, and an Astra-Zeneca Award (all to O.I.); funding from the Foundation for Science and Technology (FCT), Portugal (to P.A.G.); MICINN CTQ-2010-20960-CO2-02 (to P.L-L.); and NIHR01 DK075850 (to G.S.).Peer Reviewe

Hypoxia onducible factor (HIF) promotes reductive carboxylation in vivo and renders VHL-deficient cells sensitive to glutamine deprivation

Resumen del póster presentado al Keystone Symposium on PI 3-Kinase and Interplay with Other Signaling Pathways celebrado en Keystone-Colorado (US) del 24 de febrero al 1 de marzo de 2013.Hypoxia is a hallmark of tumor microenvironment. We showed before taht exposure of cells to hypoxia reprograms cell metabolism and directs and IDH1-mediated reductive carboxylation (RC) of glutamine-derived alpha-ketoglutarate (a-KG) for lipogenesis. In addition, Von Hippel-Lindau (VHL)-deficient renal cell carcinoma (RCC) cells use glutamine to generate citrate and lipids through RC of a-KG. to gain insights into the role of HIF and the molecular mechanisms underlying RC we took advantage of a panel of disease-associated VHL mutants and showed that HIF expression is necessary and sufficient for the induction of RC in human RCC cells. Expression of a VHL-independent HIF mutant in VHL-restored RCC cells is sufficient to promote RC. HIF expression drastically reduces intracellular citrate levels. Feeding VHL-deficient RCC cells with acetate or citrate, or knocking-down PDK-1 and ACLY enzymes restored intracellularcitrate levels and suppressed RC. These data suggest that HIF-induced low intracellular citrate levels promote the reductive flux by mass action, to maintain lipogenesis. Expression of HIF renders hypoxic and VHL-deficient cells addicted to glutamine in vitro. Systemic administration of glutaminase inhibitor (BPTES) suppressed the growth of VHL-deficient human RCC cell lines as xenografts in nude mice. Lastly, we investigated whether RC occurs in vivo. We metabolically labeled mice bearing VHL-deficient tumors by infusing them with 13C-1Glutamine for up to 6 hours and we detected the early formation of labeled citrate in the tumors; thus whe showed for the first time RC in vivo. Our data provide mechanistic insights into the signaling events that mediate hypoxia-induced RC, strongly suggest that RC is an in vivo phenomenon in growing tumors and highlight potential novel therapeutic approaches for treatment of hypoxic and VHL-deficient tumors based on this metabolic signature.Peer reviewe