Clearance or control of pathogens or tumors usually requires T-cell-mediated immunity. As such, understanding the mechanisms that govern the function, maintenance, and persistence of T cells will likely lead to new treatments for controlling disease. During an immune response, T-cell development is marked by striking changes in metabolism. There is a growing appreciation that these metabolic changes underlie the capacity of T cells to perform particular functions, and this has led to a recent focus on the idea that the manipulation of cellular metabolism can be used to shape adaptive immune responses. Although interest in this area has grown in the last few years, a full understanding of the metabolic control of T-cell functions, particularly during an immune response in vivo, is still lacking. In this review, we first provide a basic overview of metabolism in T cells, and then we focus on recent studies providing new or updated insights into the regulation of metabolic pathways and how they underpin T-cell differentiation and memory T-cell development.
T cell; metabolism; immune response
Cancer cells need to meet the metabolic demands of rapid cell growth within a continually changing microenvironment. Genetic mechanisms for reprogramming cellular metabolism toward proliferative, pro-survival pathways are well-reported. However, post-translational mechanisms, which would enable more rapid, reversible adaptations of cellular metabolism in response to protein signaling or environmental sensing systems, are less well understood. Here we demonstrate that the post-translational modification O-linked β-N-acetylglucosamine (O-GlcNAc) is a key metabolic regulator of glucose metabolism. O-GlcNAc is dynamically induced at Ser529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibits PFK1 activity and redirects the flux of glucose from glycolysis through the pentose phosphate pathway (PPP), thereby conferring a selective growth advantage to cancer cells. Blocking glycosylation of PFK1 at Ser529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. These studies reveal an unexpected mechanism for the regulation of metabolic enzymes and pathways, and pinpoint a new therapeutic approach for combating cancer.
Upon activation, quiescent naive T cells undergo a growth phase followed by massive clonal expansion and differentiation that are essential for appropriate immune defense and regulation. Accumulation of cell biomass during the initial growth and rapid proliferation during the expansion phase is associated with dramatically increased bioenergetic and biosynthetic demands. This not only requires a metabolic rewiring during the transition between resting and activation, but also ‘addicts’ active T cells to certain metabolic pathways in ways that naive and memory T cells are not. We consider such addiction in terms of the biological effects of deprivation of metabolic substrates or inhibition of specific pathways in T cells. In this review, we illustrate the relevant metabolic pathways revealed by recent metabolic flux analysis and discuss the consequences of metabolic intervention on specific metabolic pathways in T lymphocytes.
metabolism; T lymphocytes; T-cell activation
Adaptive immunity has evolved as a very powerful and highly specialized tool of host defense. Its classical protagonists are lymphocytes of the T- and B-cell lineage. Cytokines and chemokines play a key role as effector mechanisms of the adaptive immunity. Some autoimmune and inflammatory diseases are caused by disturbance of the adaptive immune system. Recent advances in understanding the pathogenesis of autoimmune diseases have led to research on new molecular and therapeutic targets. PPARγ are members of the nuclear receptor superfamily and are transcription factors involved in lipid metabolism as well as innate and adaptive immunity. PPARγ is activated by synthetic and endogenous ligands. Previous studies have shown that PPAR agonists regulate T-cell survival, activation and T helper cell differentiation into effector subsets: Th1, Th2, Th17, and Tregs. PPARγ has also been associated with B cells. The present review addresses these issues by placing PPARγ agonists in the context of adaptive immune responses and the relation of the activation of these receptors with the expression of cytokines involved in adaptive immunity.
Organisms have to continuously adapt to changing environmental conditions or undergo developmental transitions. To meet the accompanying change in metabolic demands, the molecular mechanisms of adaptation involve concerted interactions which ultimately induce a modification of the metabolic state, which is characterized by reaction fluxes and metabolite concentrations. These state transitions are the effect of simultaneously manipulating fluxes through several reactions. While metabolic control analysis has provided a powerful framework for elucidating the principles governing this orchestrated action to understand metabolic control, its applications are restricted by the limited availability of kinetic information. Here, we introduce structural metabolic control as a framework to examine individual reactions' potential to control metabolic functions, such as biomass production, based on structural modeling. The capability to carry out a metabolic function is determined using flux balance analysis (FBA). We examine structural metabolic control on the example of the central carbon metabolism of Escherichia coli by the recently introduced framework of functional centrality (FC). This framework is based on the Shapley value from cooperative game theory and FBA, and we demonstrate its superior ability to assign “share of control” to individual reactions with respect to metabolic functions and environmental conditions. A comparative analysis of various scenarios illustrates the usefulness of FC and its relations to other structural approaches pertaining to metabolic control. We propose a Monte Carlo algorithm to estimate FCs for large networks, based on the enumeration of elementary flux modes. We further give detailed biological interpretation of FCs for production of lactate and ATP under various respiratory conditions.
Insight into the functioning of metabolic control to meet changing demands is a first step in rational engineering of biological systems towards a desired behavior. Metabolic control analysis provides the means to examine the impact of change of reaction fluxes on a specific target flux based on kinetic modeling, but suffers from limitations of the kinetic approach. Here, we introduce and analyze structural metabolic control as a framework to overcome these limitations. We utilize functional centrality, a framework based on the Shapley value from cooperative game theory and flux balance analysis, to determine the contribution of individual reactions to the functions accomplished by a metabolic network. These contributions, in turn, depend on the control exerted on the remaining network. Functional centrality provides the mathematical means to gain further understanding of metabolic control. The potential applications range from facilitating strategies of rational strain design to drug target identification.
T lymphocytes regulate nutrient uptake to meet the metabolic demands of immune activation. The present study shows that the intracellular supply of large neutral amino acids (LNAAs) in T cells is regulated by pathogen and the T cell antigen receptor (TCR). A single System L transporter, Slc7a5, mediated LNAA uptake in activated T cells. Slc7a5-null T cells could not metabolically reprogram in response to antigen and failed clonal expansion and effector differentiation. The metabolic catastrophe caused by Slc7a5 loss reflects the requirement for sustained uptake of the LNAA leucine for activation of mammalian target of rapamycin complex 1 (mTORC1) and for expression of c-myc. Pathogen control of System L transporters is thus a critical metabolic checkpoint for T cells.
It has been long appreciated that protective immunity against fungal pathogens is dependent on activation of cellular adaptive immune responses represented by T lymphocytes. The T-helper (Th)1/Th2 paradigm has proven to be essential for the understanding of protective adaptive host responses. Studies that have examined the significance of regulatory T cells in fungal infection, and the recent discovery of a new T-helper subset called Th17 have provided crucial information for understanding the complementary roles played by the various T-helper lymphocytes in systemic versus mucosal antifungal host defense. This review provides an overview of the role of the various T-cell subsets during fungal infections and the reciprocal regulation between the T-cell subsets contributing to the tailored host response against fungal pathogens.
T helper cells; Gamma delta T cells; Cytotoxic T cells; Regulatory T cells; Th1; Th17; Th2; Fungal infection; Candida; Aspergillus; Histoplasma; Pneumocystis; Cryptococcus; IL-17; Interferon gamma; IL-4; IL-10; Plasticity; Interaction; Adaptive immunity; Cytokine responses
The heart is one of the highest ATP consuming organs in mammalian organisms. Its metabolic function has evolved a remarkable degree of efficiency to meet high demand and plasticity in response to varying changes in energy substrate supply. Given the high flux of energy substrates and the centrality of their appropriate use for optimal cardiac function, it is not surprising that the heart has intricate signaling mechanisms through which it responds to metabolic stress. This review focuses on the changes in gene expression in myocardial and vascular tissues during metabolic stress that affect mRNAs and subsequent protein synthesis with an eye toward understanding the manner in which these changes effect adaptive and maladaptive responses of the heart.
diabetic cardiomyopathy; pathological hypertrophy; ischemia-reperfusion; nutrient deprivation; metabolic adaptation and maladaptation; nuclear receptor transcription factor; histone deacetylation; miRNA; protein translation
Inadequate β-cell mass can lead to insulin insufficiency and diabetes. During times of prolonged metabolic demand for insulin, the endocrine pancreas can respond by increasing β-cell mass, both by increasing cell size and by changing the balance between β-cell proliferation and apoptosis. In this paper, we review recent advances in our understanding of the mechanisms that control the adaptive expansion of β-cell mass, focusing on the islet’s response to pregnancy, a physiological state of insulin resistance. Functional characterization of factors controlling both β-cell proliferation and survival might not only lead to the development of successful therapeutic strategies to enhance the response of the β-cell to increased metabolic loads, but also improve islet transplantation regimens.
Cells generate ATP by glycolysis and by oxidative phosphorylation (OXPHOS) (1, 2). Despite the importance of having sufficient ATP available for the energy-dependent processes involved in immune activation, little is known about the metabolic adaptations that occur in vivo to meet the increased demand for ATP in activated and proliferating lymphocytes. We found that bone marrow (BM) cells proliferating after bone marrow transplantation (BMT) increased aerobic glycolysis but not OXPHOS, while T cells proliferating in response to alloantigens during graft versus host disease (GVHD) increased both aerobic glycolysis and OXPHOS. Metabolomic analysis of alloreactive T cells showed an accumulation of acylcarnitines consistent with changes in fatty acid oxidation. Alloreactive T cells also exhibited a hyperpolarized mitochondrial membrane potential (ΔΨm), increased superoxide production and decreased antioxidant levels, whereas proliferating BM cells did not. Bz-423, a novel small molecule inhibitor of the mitochondrial F1F0-ATPase, selectively increased superoxide and induced the apoptosis of alloreactive T cells, which arrested established GVHD in several BMT models without affecting hematopoietic engraftment or lymphocyte reconstitution. These findings challenge the current paradigm that activated T cells meet their increased demands for ATP though aerobic glycolysis, and identify the possibility that bioenergetic and redox characteristics can be selectively exploited as a novel therapeutic strategy for immune disorders.
The orchestrated movement of cells of the immune system is essential to generation of productive responses leading to protective memory development. Recent advances have allowed the direct microscopic visualization of lymphocyte and antigen-presenting cell migration and interaction during immune response initiation and progression. These studies have defined important characteristics of the microanatomy of lymphocyte movement, particularly in the lymph node. Moreover, the ability to track endogenous antigen-specific T cells has revealed a coordinated pathway of CD8 T cell movement in the spleen following primary and secondary infection. As a consequence, the local anatomy of secondary lymphoid tissues during infection has emerged as a critical regulator of immunity. While some of the factors responsible for the migratory cues instructing immune cell movement have been identified, much remains to be learned. Here, we provide a brief overview of our studies examining CD8 T cell localization during the immune response to infection in the context of our current understanding of immune system structure.
infection; T cell; migration; imaging; memory
Hepatic inflammation is a common finding during a variety of liver diseases including drug-induced liver toxicity. The inflammatory phenotype can be attributed to the innate immune response generated by Kupffer cells, monocytes, neutrophils, and lymphocytes. The adaptive immune system is also influenced by the innate immune response leading to liver damage. This review summarizes recent advances in specific mechanisms of immune-mediated hepatotoxicity and its application to drug-induced liver injury. Basic mechanisms of activation of lymphocytes, macrophages, and neutrophils and their unique mechanisms of recruitment into the liver vasculature are discussed. In particular, the role of adhesion molecules and various inflammatory mediators in this process are explored. In addition, the authors describe mechanisms of liver cell damage by these inflammatory cells and critically evaluate the functional significance of each cell type for predictive and idiosyncratic drug-induced liver injury. It is expected that continued advances in our understanding of immune mechanisms of liver injury will lead to an earlier detection of the hepatotoxic potential of drugs under development and to an earlier identification of susceptible individuals at risk for predictive and idiosyncratic drug toxicities.
adverse drug reactions; hepatotoxicity; immune-mediated liver injury; idiosyncratic liver toxicity; lymphocytes; macrophages; neutrophils; innate immunity
Metabolic reprogramming is a key event in tumorigenesis to support cell growth, and cancer cells frequently become both highly glycolytic and glutamine dependent. Similarly, T lymphocytes (T cells) modify their metabolism after activation by foreign antigens to shift from an energetically efficient oxidative metabolism to a highly glycolytic and glutamine-dependent metabolic program. This metabolic transition enables T cell growth, proliferation, and differentiation. In both activated T cells and cancer cells metabolic reprogramming is achieved by similar mechanisms and offers similar survival and cell growth advantages. Activated T cells thus present a useful model with which to study the development of tumor metabolism. Here, we review the metabolic similarities and distinctions between activated T cells and cancer cells, and discuss both the common signaling pathways and master metabolic regulators that lead to metabolic rewiring. Ultimately, understanding how and why T cells adopt a cancer cell-like metabolic profile may identify new therapeutic strategies to selectively target tumor metabolism or inflammatory immune responses.
Cancer; Lymphocyte; Metabolism; Aerobic glycolysis
Only a handful of the more than 100,000 fungal species on our planet cause disease in humans, yet the number of life-threatening fungal infections in patients has recently skyrocketed as a result of advances in medical care that often suppress immunity intensely. This emerging crisis has created pressing needs to clarify immune defense mechanisms against fungi, with the ultimate goal of therapeutic applications. Herein, we describe recent insights in understanding the mammalian immune defenses deployed against pathogenic fungi. The review focuses on adaptive immune responses to the major medically important fungi and emphasizes how dendritic cells and subsets in various anatomic compartments respond to fungi, recognize their molecular patterns, and signal responses that nurture and shape the differentiation of T cell subsets and B cells. Also emphasized is how the latter deploy effector and regulatory mechanisms that eliminate these nasty invaders while also constraining collateral damage to vital tissue.
dendritic cells; pattern-recognition receptors; T lymphocytes; chemokines; chemokine receptors
Natural killer (NK) cells, the CD3- CD56+ CD16+ subset of peripheral blood lymphocytes, have long been known to be involved in non-major histocompatibility complex-restricted natural immunity to virally infected and malignant target cells. The association of abnormalities in NK cell numbers or functions with a broad spectrum of human diseases has been more clearly defined in recent years as a result of the improved knowledge of NK cell physiology and advances in monitoring of NK cell functions in health and disease. The ability to reliably measure changes in NK activity and/or numbers during the course of disease or response to treatment has focused attention on the role of the NK cell in disease pathogenesis. The improved understanding of NK cell deficiency in disease has opened a way for therapies specifically designed to improve NK cell function. The therapeutic use of biologic response modifiers capable of augmenting NK cell activity in vivo and of adoptive transfer of highly enriched, activated autologous NK cells in diseases such as cancer and AIDS is being evaluated. The importance of NK cells in health and the consequences of NK cell deficiency or excess are likely to be more extensively monitored in the future.
The regulation of lymphocyte homeostasis is critical for the development and formation of productive immune responses. Cell numbers must be maintained to allow sufficient numbers of lymphocytes to combat foreign pathogens but prevent the accumulation of excess lymphocytes that may increase the risk of developing autoimmunity or neoplasia. Cell extrinsic growth factors are essential to maintain homeostasis and cell survival, and it has become increasingly apparent that a key mechanism of this control is through regulation of cell metabolism. The metabolic state of T cells can have profound influences on cell growth and survival and even differentiation. In particular, resting T cells utilize an energy efficient oxidative metabolism but shift to a highly glycolytic metabolism when stimulated to grow and proliferate by pathogen encounter. After antigen clearance, T cells must return to a more quiescent oxidative metabolism to support T-cell memory. This review highlights how these metabolic changes may be intricately involved with both T-cell growth and death in the control of homeostasis and immunity.
T cells; cytokine receptors; T-cell receptors; cell activation; autophagy/apoptosis; signal transduction
Newly activated CD8+ T cells reprogram their metabolism to meet the extraordinary biosynthetic demands of clonal expansion; however, the signals mediating metabolic reprogramming remain poorly defined. Herein, we demonstrate an essential role for sterol regulatory element binding proteins (SREBPs) in the acquisition of effector cell metabolism. Without SREBP signaling, CD8+ T cells are unable to blast, resulting in markedly attenuated clonal expansion during viral infection. Mechanistic studies indicate that SREBPs are essential to meet the heightened lipid requirements of membrane synthesis during blastogenesis. SREBPs are dispensable for homeostatic proliferation, indicating a context-specific requirement for SREBPs in effector responses. These studies provide insights into the molecular signals underlying metabolic reprogramming of CD8+ T cells during the transition from quiescence to activation.
SREBP; LCMV; lipids; CD8+ T cell; metabolism; proliferation
Gut microbiota have recently been implicated in the pathogenesis of the obesity and its related metabolic diseases. Avariety of factors including diet, genetic background, environment and host innate and adaptive immune responses define an individual’s gut microbiota. In this review we outline potential mechanisms by which gut microbiota can contribute to the development of obesity focusing on specific processes such as microbial energy extraction, microbiota induced-inflammation and regulation of appetite. We review the current understanding of each of these processes on regulating metabolism and examine potential therapeutic strategies for the treatment or prevention of the metabolic syndrome. We explore the hypothesis that alteration in gut microbiota may be an initial event leading to altered feeding behavior and/or systemic inflammation, ultimately leading to weight gain and the metabolic syndrome.
The adaptive immune response relies on the ability of lymphocytes to undergo periodic massive expansion. It is an enigma how lymphocytes are able to undergo this seemingly unlimited number of cell divisions. Telomeres and telomerase play a critical role in regulation of the replicative lifespan of cells, providing a potential mechanism which lymphocytes may employ. Here I will review the recent progress of the role of telomeres and telomerase in lymphocyte differentiation, function, and aging.
Human; Telomere; Telomerase; Aging; T cells; B cells
The adenosine monophosphate-activated protein kinase (AMPK) is activated by antigen receptor signals and energy stress in T cells. In many cell types, AMPK can maintain energy homeostasis and can enforce quiescence to limit energy demands. We consequently evaluated the importance of AMPK for controlling the transition of metabolically active effector CD8 T lymphocytes to the metabolically quiescent catabolic memory T cells during the contraction phase of the immune response. We show that AMPKα1 activates rapidly in response to the metabolic stress caused by glucose deprivation of CD8 cytotoxic T lymphocytes (CTLs). Moreover, AMPKα1 restrains mammalian target of rapamycin complex 1 activity under conditions of glucose stress. AMPKα1 activity is dispensable for proliferation and differentiation of CTLs. However, AMPKα1 is required for in vivo survival of CTLs following withdrawal of immune stimulation. AMPKα1null T cells also show a striking defect in their ability to generate memory CD8 T-cell responses during Listeria monocytogenes infection. These results show that AMPKα1 monitors energy stress in CTLs and controls CD8 T-cell memory.
Cytotoxic T lymphocyte; Energy stress; Listeria monocytogenes; Memory; Metabolism
Somatic cell reprogramming has dramatically changed stem cell research in recent years. The high pace of new findings in the field and an ever increasing amount of data from new high throughput techniques make it challenging to isolate core principles of the process. In order to analyze such mechanisms, we developed an abstract mechanistic model of a subset of the known regulatory processes during cell differentiation and production of induced pluripotent stem cells. This probabilistic Boolean network describes the interplay between gene expression, chromatin modifications, and DNA methylation. The model incorporates recent findings in epigenetics and partially reproduces experimentally observed reprogramming efficiencies and changes in methylation and chromatin remodeling. It enables us to investigate, how the temporal progression of the process is regulated. It also explicitly includes the transduction of factors using viral vectors and their silencing in reprogrammed cells, since this is still a standard procedure in somatic cell reprogramming. Based on the model we calculate an epigenetic landscape for probabilities of cell states. Simulation results show good reproduction of experimental observations during reprogramming, despite the simple structure of the model. An extensive analysis and introduced variations hint toward possible optimizations of the process that could push the technique closer to clinical applications. Faster changes in DNA methylation increase the speed of reprogramming at the expense of efficiency, while accelerated chromatin modifications moderately improve efficiency.
differentiation and reprogramming; epigenetic landscape; induced pluripotent stem cells; mathematical modeling; probabilistic Boolean network
Expansion of aquaculture is seriously limited by reductions in fish oil (FO) supply for aquafeeds. Terrestrial alternatives such as vegetable oils (VO) have been investigated and recently a strategy combining genetic selection with changes in diet formulations has been proposed to meet growing demands for aquaculture products. This study investigates the influence of genotype on transcriptomic responses to sustainable feeds in Atlantic salmon.
A microarray analysis was performed to investigate the liver transcriptome of two family groups selected according to their estimated breeding values (EBVs) for flesh lipid content, 'Lean' or 'Fat', fed diets containing either FO or a VO blend. Diet principally affected metabolism genes, mainly of lipid and carbohydrate, followed by immune response genes. Genotype had a much lower impact on metabolism-related genes and affected mostly signalling pathways. Replacement of dietary FO by VO caused an up-regulation of long-chain polyunsaturated fatty acid biosynthesis, but there was a clear genotype effect as fatty acyl elongase (elovl2) was only up-regulated and desaturases (Δ5 fad and Δ6 fad) showed a higher magnitude of response in Lean fish, which was reflected in liver fatty acid composition. Fatty acid synthase (FAS) was also up-regulated by VO and the effect was independent of genotype. Genetic background of the fish clearly affected regulation of lipid metabolism, as PPARα and PPARβ were down-regulated by the VO diet only in Lean fish, while in Fat salmon SREBP-1 expression was up-regulated by VO. In addition, all three genes had a lower expression in the Lean family group than in the Fat, when fed VO. Differences in muscle adiposity between family groups may have been caused by higher levels of hepatic fatty acid and glycerophospholipid synthesis in the Fat fish, as indicated by the expression of FAS, 1-acyl-sn-glycerol-3-phosphate acyltransferase and lipid phosphate phosphohydrolase 2.
This study has identified metabolic pathways and key regulators that may respond differently to alternative plant-based feeds depending on genotype. Further studies are required but data suggest that it will be possible to identify families better adapted to alternative diet formulations that might be appropriate for future genetic selection programmes.
Biological systems are integrated networks constantly responding to internal and external stimulators. Understanding the intrinsic response to an imbalanced system provides the opportunity to develop therapeutic approaches to reinstate the natural balanced state. Increasing evidence suggests that members of the nuclear receptor superfamily integrate both inflammatory and metabolic signals to maintain homeostasis in immune cells such as macrophages and lymphocytes. PPAR and LXR are nuclear receptors activated by fatty acid and cholesterol derivatives respectively that control the expression of an array of genes involved in lipid metabolism and inflammation. Recent studies have uncovered distinct mechanisms for transcriptional regulation of metabolic and inflammatory target genes by PPAR and LXR and have expanded the biology of these receptors to include roles in alternative macrophage activation and adaptive immunity.
Somatic cells can be reprogrammed to a pluripotent state through the ectopic expression of defined transcription factors. Understanding the mechanism and kinetics of this transformation may shed light on the nature of developmental potency and suggest strategies with improved efficiency or safety. Here we report an integrative genomic analysis of reprogramming of mouse fibroblasts and B lymphocytes. Lineage-committed cells show a complex response to the ectopic expression involving induction of genes downstream of individual reprogramming factors. Fully reprogrammed cells show gene expression and epigenetic states that are highly similar to embryonic stem cells. In contrast, stable partially reprogrammed cell lines show reactivation of a distinctive subset of stem-cell-related genes, incomplete repression of lineage-specifying transcription factors, and DNA hypermethylation at pluripotency-related loci. These observations suggest that some cells may become trapped in partially reprogrammed states owing to incomplete repression of transcription factors, and that DNA de-methylation is an inefficient step in the transition to pluripotency. We demonstrate that RNA inhibition of transcription factors can facilitate reprogramming, and that treatment with DNA methyltransferase inhibitors can improve the overall efficiency of the reprogramming process.
Immunological function requires metabolic support to suit the needs of lymphocytes at a variety of distinct differentiation and activation states. It is now evident that the signaling pathways that drive lymphocyte survival and activity can directly control cellular metabolism. This linkage provides a mechanism by which activation and specific signaling pathways provide a supply of appropriate and required nutrients to support cell functions in a pro-active supply rather than consumption-based metabolic model. In this way, the metabolism and fuel choices of lymphocytes are guided to specifically match the anticipated needs. If the fuel choice or metabolic pathways of lymphocytes are dysregulated, however, metabolic checkpoints can become activated to disrupt immunological function. These changes are now shown in several immunological diseases and may open new opportunities to selectively enhance or suppress specific immune functions through targeting of glucose, lipid, or amino acid metabolism.
Lymphocyte; glycolysis; mitochondria; apoptosis