Year: 2012
Type: review
Abstract: This article introduces a series of reviews covering Metabolism and Autophagy in the Immune System appearing in Volume 249 of Immunological Reviews. Two of the most fundamental ways in which cells and animals interact with their environment are through obtaining nutrients sufficient to sustain life and defending against attack of potentially pathogenic organisms. It is not surprising with some reflection, therefore, that immune cell metabolism and function are linked and that the immune system as a whole is connected and closely interacts with basic metabolic tissues and processes. This basic premise is now well accepted, but, until recently, was overlooked in both studies of the immune system and in studies of nutrition and metabolism. It had been apparent nearly one hundred years ago, however, that nutrition and immunological state could be associated, as malnutrition was clearly defined as an immunosuppressive condition, with increased infections in poorly fed populations1, 2. Evolutionarily, it appears that the highly energy-dependent process of immune protection was simply selected as a system to be quickly sacrificed in times of famine, so as to maintain enough energy for immediately vital functions, such as neuronal and cardiovascular systems. This nutrition and immunity association now provides context for the rise of immunometabolism as a field. Current thinking acknowledges that the links between immunity and metabolism are not limited to malnutrition and include basic cellular processes as well as close interactions between immune cells and metabolic tissues. In particular, immune responses are highly energy dependent, and how lymphocytes obtain their energy offers a new approach to modify immunity and define specific immune functions. Metabolic stress response pathways, such as autophagy, are also intimately tied to immunity, to activate the innate immune response, to allow adaptive immunity, as well as to directly eliminate some pathogens. In addition, the growing incidence of obesity and the metabolic syndrome in the western world are now known to have inflammation and overactive immunity as a root source of pathology. As recognition of the importance of these areas grows, the field of immunometabolism is now of broad importance in basic biologic understanding of immunity as well as in a variety of pathological settings. This volume includes reviews to discuss current literature and thought on each of these topics and to point toward future directions how metabolic links with immunity ultimately may be exploited to treat a wide array of metabolic and immunologic diseases. One of the first criteria for proper immunity is that the immunologic cells themselves must have appropriate and sufficient energy to support their demands. The study of regulation of cell metabolism in the immune system was of great interest in the past and has re-emerged in recent years to better understand basic biology of immunity as well as transformation. One of the earliest pioneers of this work on leukocyte metabolism, not surprisingly, was the noted Otto Warburg. Warburg showed that glycolysis rather than oxidative metabolism is the favored metabolic program for stimulated leukocytes 3. This study followed a series of seminal papers by Warburg starting in the 1920s that showed cancer metabolism was highly characterized by a transition from an aerobic oxidative metabolism to glycolysis, even in the presence of oxygen. This metabolic program is now found in a wide range of cancers and is termed aerobic glycolysis 4. Warburg's essential finding, therefore, was that stimulated leukocytes are metabolically similar to cancer cells and favor glycolysis over mitochondrial oxidative pathways. Others soon followed to also measure how leukocyte activation increased anaerobic glucose metabolism 5, 6, including detailed NMR flux analyses of T-cell activation that showed increased glycolysis as well as glutamine oxidation 7. It has been evident, therefore, that lymphocyte activation leads to a metabolic reprogramming similar to cancer cells as far back as the 1950s and 1960s. The driving force behind the transition of a resting lymphocyte from an oxidative to a highly glycolytic metabolism is to support the change in cellular metabolic demands to support immunity. Cell metabolism must fundamentally meet the functional requirements of the cell. Resting cells are quiescent and require primarily adenosine triphosphate (ATP) for basal cell functions and energy-demanding process of chemotaxis in immune surveillance. Upon stimulation, however, lymphocytes enter the cell cycle and can divide as often as every 4–6 h 8, 9. In this state, lymphocytes require both ATP and tremendous quantities of biosynthetic precursors to support rapid growth. Oxidative metabolism is highly efficient at generating energy, but converting carbon sources to carbon dioxide for ATP production leaves little capacity for macromolecular synthesis. Glycolysis coupled with glutamine metabolism, however, can provide both ATP and intermediates for nucleotide, lipid, and amino acid synthesis 10. At the end of an immune response, T cells no longer require rapid growth and decrease glycolytic metabolism as cells are selected for long-term immunological memory. Memory T cells have been shown to revert to oxidation of lipids as primary energy source 11, 12. The transition of T cells from oxidative to glycolytic and back to oxidative metabolism is reviewed by Van Der Windt and Pearce 13. Ultimately, the ability of cells to undergo these metabolic transitions may link tightly to cell survival and the ability of antigen-specific T-cell clones to rapidly expand to allow competitive selection of high-affinity clones 14-16 and is reviewed by Wensveen et al. 17. The details of this metabolic transition are now becoming apparent and may provide new directions to modulate immunity (Fig. 1). With similar metabolic demands to maximally support cell growth of both cancer cells and stimulated lymphocytes, the field of cancer metabolism has provided important metabolic clues to understand immune function. Also, because the key signaling pathways that stimulate an immune response are often oncogenic when constitutively active, it is now apparent that the molecular signals that promote aerobic glycolysis are shared between these otherwise potentially quite disparate populations. In normal cells, signals to promote metabolism are initiated by cell extrinsic stimuli, such as cytokines or antigen receptor stimulation. Indeed, even resting T cells require cell extrinsic signals to maintain basal rates of metabolism 18. Of these signals in resting cells, conditional deletion of the interleukin-7 (IL-7) receptor showed this pathway to be essential to maintain basal glucose metabolism in vivo 19. T-cell receptor and CD28 costimulation can then lead to a rapid and dramatic increase in metabolism and transition to aerobic glycolysis 20. The molecular and metabolic details of this switch in acute T-cell activation are now becoming apparent and are reviewed by Wang and Green 21. Chronic T-cell activation, such as in autoimmunity or in graft versus host disease, may lead to a different metabolic phenotype, with T cells reverting from aerobic glycolysis back to favor a more oxidative metabolism 22. Wahl et al. 23 review these metabolic changes and the potential of specifically targeting the oxidative metabolism of chronically stimulated T cells in inflammatory diseases. Three main signaling mechanisms have been identified to drive aerobic glycolysis in T-cell activation. In each case, pathway activation frequently occurs in cancer due to oncogenic mutations or as a result of cell receptor signals in T cells. The phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is activated in a wide range of cancers and in T-cell activation and is reviewed by Waickman and Powell 24. This pathway plays a major role to promote anabolic metabolism. Activation of the PI3K/Akt/mTOR pathway promotes Glut1 trafficking to the cell surface 25 to drive glucose uptake and glycolysis and also leads to increased protein translation and induction of the transcription factor SREBP1 that stimulates lipid synthesis 26. If mTOR complex 1 (mTORC1) is inhibited, T cells fail to switch to aerobic glycolysis or grow and instead become tolerized or anergic. Interestingly, anergic T cells remain metabolically oxidative and blocking aerobic glycolysis itself appears sufficient to drive, in turn, T-cell anergy 27. Upstream of mTORC1, PI3K produces phosphatidylinositol-3 phosphate that activates phosphoinositide-dependent kinase 1 (PDK1), which then phosphorylates Akt to promote activation of this kinase. This signaling pathway is not entirely linear, however, as PDK1 may also have roles to regulate glucose metabolism in mechanisms both dependent and independent of Akt 28. Opposing the PI3K/Akt/mTOR pathway is 5′AMP-activated protein kinase (AMPK), which inhibits mTORC1 and stimulates catabolic rather than anabolic metabolic pathways to promote glucose and lipid oxidation 29. AMPK is activated by elevated ratio of AMP or ADP to ATP and by tumor suppressor LKB1 or CamKKβ. The roles of LKB1 and AMPK in immunity are complex, but appear to both play roles in survival and maintaining immune homeostasis 30-32. Given the prevalence of AMPK activating drugs, such as metformin, as treatments in obesity and Type II diabetes, it is important to better understand the role of this kinase in T-cell metabolism and function. It is possible that some or even many of the symptoms of the metabolic syndrome that are relieved by these drugs are mediated through direct modulation of immune cell metabolism rather than indirectly through generally improved metabolic health and this topic is reviewed in Blagih et al. 33. A second key pathway that promotes aerobic glycolysis in lymphocytes is through induction of the oncogenic transcription factor, c-Myc. c-Myc is highly associated with a wide variety of cancers and has been shown to induce both glycolytic genes as well as genes essential for glutamine metabolism 34. c-Myc is also rapidly upregulated upon T-cell activation. Recently, conditional c-Myc deletion in T cells showed this factor essential for increased expression of nearly all genes involved in glycolysis, and glutaminolysis, and other pathways, including the polyamine pathway 35. As a consequence of this prominent regulatory role, c-Myc-deficient T cells failed to grow and were unable to proliferate. As reviewed by Wang and Green 21, it is critical that dividing cells have appropriate metabolic support, and there is a growing appreciation that c-Myc plays a central role to promote metabolic pathways to meet the needs of proliferative cells. Stimulation of the glutamine oxidative pathway may be a particularly important for c-Myc, as glutamine is essential to maintain anapleurotic flux through the tri-carboxylic cycle (TCA) in rapidly growing cells. By stimulating this pathway, however, c-Myc can render cells glutamine dependent 34, a finding that may be exploited in cancer therapies and could also have impact in immunosuppression. A third class of proteins shown to regulate T-cell metabolism are nuclear hormone receptors. As reviewed by Kidani and Bensinger 36, the liver X receptor (LXR), peroxisome proliferator-activated receptors (PPARs), and estrogen-related receptor-α (ERRα) can play key roles in lymphocyte metabolic regulation. Most strikingly, LXR-deficient T cells have increased activation, leading to elevated proliferation and production of inflammatory cytokines 37. LXR normal opposes SREBP action and promotes the efflux of cholesterol, whereas SREBP promotes lipid and cholesterol synthesis. LXR-deficient T cells, therefore, have excess cholesterol and sterol generation and accumulation that can drive T-cell inflammatory function. PPARs (PPARα, β/δ, γ) promote lipid metabolic pathways and lipid oxidation by inducing genes such as carnitine palmitoyl transferase 1a (CPT1a), a rate-limiting component of lipid oxidation. CPT1a is also upregulated as CD8+ T cells switch from proliferating effectors using glycolysis to memory cells dependent on lipid oxidation 38. Consistent with promoting oxidation of lipids rather than lipid synthesis for cell growth, synthetic PPAR ligands have been used to treat metabolic disease and have immunosuppressive properties. Lastly, ERRα is well known to promote a variety of metabolic pathways, including the TCA cycle and mitochondrial electron transport 39, and is upregulated in T-cell activation 40 and macrophage function 41. ERRα expression is associated with poor prognosis in a variety of cancers 42 and has also been shown to be important for carbohydrate metabolism in developing Drosophila 43. ERRα is essential for macrophage metabolism and protection against Listeria monocytogenes 41, and our laboratory recently showed a key role for ERRα to coordinate mitochondrial and glucose metabolism in proliferating lymphocytes. Inhibition of this pathway can suppress immunity and an experimental autoimmune encephalomyelitis (EAE) response 40. Because metabolism must match cell function, it is not surprising that T cells with distinct immunological roles utilize specific metabolic programs 9. A key clue to define these pathways was the finding that conditional deletion of mTOR in mature CD4+ T cells allowed only the generation of regulatory T cells (Tregs) 44. Further studies to specifically modify the mTORC1 and mTORC2 pathways also led to selective generation of T-cell subsets, with mTORC1 essential for Th1 and Th17 cells while mTORC2 was essential for Th2 45, 46. This topic is reviewed in detail by Waickman and Powell 24. Given the clear role for mTOR to promote glucose uptake and glycolysis 26, we reasoned that Tregs and effector [T-helper 1 (Th1), Th2, Th17] CD4+ T cells may differ metabolically. Indeed, while all stimulated CD4+ T cells are more metabolically active than resting cells, Tregs are reliant on lipid oxidation for a primary metabolic fuel, whereas effectors utilize glucose and glutamine oxidation 47. Consistent with a role for AMPK to promote oxidative metabolism and antagonize mTORC1, phospho-AMPK levels were elevated in both induced and natural Treg and in vivo stimulation of AMPK could both decrease glucose metabolism and increase Tregs in a model of murine asthma 47. Furthermore, targeting metabolic pathways could shift T-cell differentiation, as inhibition of glucose metabolism with 2-deoxyglucose blocked generation of Th1 and Th17 cells, but favored production of Treg both in vitro and in vivo 47, 48 and is reviewed by Wang and Green 21. In addition to mTOR and AMPK, the hypoxia inducible factor 1α (HIF1α) has been found to play a key role in generation of CD4+ T-cell subsets, but in this case, specifically Th17 cells. HIF1α is a transcription factor that is tightly regulated by oxygen availability and has a role to upregulate glycolytic genes and promote anaerobic metabolism 49, 50. Interestingly, HIF1α is highly expressed in Th17 cells but not in other CD4 lineages 48, 51. Although HIF1α deficiency does not disrupt normal T-cell activation and metabolic reprogramming in the first day or two of activation 35, HIF1αnull T cells ultimately fail to become Th17 cells even under optimal conditions 48, 51. The mechanisms by which HIF1α to promote Th17 fate is not certain and may involve increased glycolysis 48 or potentially direct biochemical regulation of the Th17 transcription factor RORγT 51. This topic is reviewed in Wang and Green 21 and may have significant implications for modulating the balance of inflammatory Th17 and suppressive Treg cells in immunity. Amino acid metabolism is also critical for lymphocyte proliferation and differentiation of T cells into effector or Treg lineages and is reviewed by McGaha et al. 52. Amino acid pathways are linked to mTOR, as mTOR is sensitive to amino acid levels and decreased amino acids suppress mTOR activation. Beyond mTOR signaling, however, availability of essential amino acids is critical for immune function through uncharged tRNA stress and other metabolic intermediates. Tryptophan catabolism, in particular, is induced through upregulation of indoleamine 2,3 dioxygenase (IDO1, IDO2) in response to inflammatory cytokines. IDO1 can promote tryptophan metabolism that can have both cell intrinsic and extrinsic effects on T cells and can both deplete tryptophan and generate metabolites with signaling properties that suppress inflammation and immunity and instead promote Treg generation. Conversely, IDO1 inhibition can increase tryptophan availability and promote immunity 53, 54. Nutrient limitation in the microenvironment is a concern of cells throughout evolution, and the process of autophagy is one of the primary responses to this stress. Autophagy involves a series of ubiquitination-like protein modifications that ultimately lead to the engulfment of cytosolic contents into double membrane lipid vesicles for transport into lysosomes. Upon fusion with lysosomes, then termed autophagolysosomes, the contents are degraded, and small molecules are into the This has the of potentially cytosolic contents as well as to generate an source of nutrients This process is reviewed in detail in et al. The metabolic role for autophagy was clearly shown in response to growth factor of cells and we have shown that cells on autophagy to provide a source of lipids for oxidative metabolism when glycolysis Autophagy has other functions as however, and as a to and a variety of including cytosolic protein and Autophagy is regulated AMPK and mTORC1 of the In and are and by nutrients become however, such as with amino acid levels or decreased of ATP to ADP or AMP that lead to AMPK activation, mTORC1 to and AMPK can directly and activate then autophagy, including processes such as mitochondrial or This may play a key role to provide an source of nutrients to promote the survival of tumor cells under metabolic stress. is a therefore, in autophagy to eliminate cancer cells. This however, may have some on immune cells and also potential immune response or other immune as reviewed by et al. It is now clear from studies that have directly autophagy in immune cells that this process plays roles in immunity. functions include and a source of nutrients to metabolically cells. Autophagy appears not only to be an important source of nutrients to support metabolism of leukocytes but also to play a prominent role in and immune Because the response is a to direct cytosolic to the this process is used to the cell of pathogens. for are in to for and inhibition of autophagy can Furthermore, it is now clear that this metabolic stress pathway is exploited in innate immunity as a to signals and the inflammatory innate immune molecular and molecular are in and are essential for normal immune protection in or as reviewed by et al. Autophagy plays a key role in lymphocyte and activation. The of this is not but and T cells fail to Further lymphocyte homeostasis and activation are This may be in due to a of lymphocytes on autophagy as a metabolic source in the of activation, when the rapid increase in metabolic may the upregulation of aerobic glycolysis and In addition, autophagy may play key roles in regulation of signaling and of excess as reviewed by et al. In particular, developing have more than mature lymphocytes and autophagy appears to play a key role to eliminate excess that otherwise appear to cells to In addition to autophagy, metabolic stress can ultimately lead to or The process of however, has of both and and is reviewed by and is induced through activation of and of receptor activation. activation can this process to induce and is most clearly in cells with As many can suppress this process may have important in host In addition, oxygen that can on cell metabolism have become apparent as a key of The link between and autophagy is not but inhibition that leads to also can promote Inhibition of in turn, The mechanisms and role of but regulation of autophagy and the of on clear to metabolism. Beyond metabolism in the immune between and immunity are becoming In particular, this topic has become of great interest as the rates of obesity and metabolic syndrome increase and a inflammation has been shown to be a driving force in of the associated nutrition and immunity are so closely linked is but as leads to immune leads to immune responses and It may be that the to energy in times of has linked immune responses to to balance the energy of immunity with needs to support processes links metabolism to the immune system through and or that can modulate immunity to promote inflammation and metabolic syndrome these links nearly all cells in the immune system and are reviewed by et al. The role of lymphocytes, in particular, as of many of the inflammatory of obesity is by that Tregs in but are decreased in as Th1 and inflammatory T-cell become favored Furthermore, CD8+ T cells may play a key role to inflammatory and T-cell can suppress T-cell activation and therefore, may be the first of inflammation and the metabolic syndrome A major with critical roles in both nutrition and immune regulation that to T-cell function and inflammation is which can promote and to In to and levels are The effects of elevated levels of this have been most apparent in with deficiency and in that or the receptor In each of these deficiency leads to metabolic with increased and leading to and also immune Conversely, in levels and metabolic that can be with Although all of the immune system are by and T cells in In particular, is known not only in metabolic regulation but also as an inflammatory promoting Th1 and Th2 CD4+ T-cell Tregs are also highly by which can suppress their et al. review the of with T cells in the immune increased and has direct impact on T-cell and function as a to link nutrition to immunity. Conversely, malnutrition which leads to T-cell and the potential of increased Treg function that may to immune In addition to lymphocytes, are key effectors of T-cell subsets, can be associated with these are and can from one to the inflammatory macrophage is termed whereas are immune regulatory and immune in tissues of and such as to maintain metabolic homeostasis through active accumulation in however, leads to a of to the phenotype, with production of inflammatory such as and The signals that this switch from to are complex, but acids themselves can promote receptor signaling and of to the glycolytic of effector T cells and oxidative of are whereas on AMPK and are oxidative et al. review signals and metabolic processes that regulate and macrophage metabolism and their roles in The and production of inflammatory cytokines can then promote in to the response and metabolic through such as which may have a particularly important role in this process as reviewed by et al. In addition to the direct activation of inflammation by lipids signaling changes in availability for lymphocytes and may also Indeed, changes in availability can in vitro differentiation of effector and Treg cells, with increased levels effector T cells while stimulating Treg 47. In changes are more complex, and obesity and and may instead promote effector inflammatory T cells. in lipid and oxidation may also be This apparent in the role of lipids to stimulate Treg in the normal state to of Treg in obesity and that metabolic disease has and complex regulation of immune cells. Indeed, the accumulation of Tregs in is with obesity and an in vivo switch that may be a key in the of inflammation and the metabolic of the role of metabolism in immunity and that immune cells play critical roles to drive the of metabolic has a of important and The association of immunity and metabolism at the most basic lymphocytes and innate immune cells energy to function. these pathways are regulated and impact T-cell function are not but blocking glucose or glutamine metabolism can lymphocyte activation and proliferation 35, 47, targeting these metabolic pathways, therefore, may provide a new in immunosuppression. Furthermore, with the distinct metabolic of effector T cells and Tregs 47, 48, and for and it may be possible to immune responses by metabolic that each T-cell specific metabolic program and or this program can or these cell functions. addition of lipids increased Treg generation by lipid whereas of Glut1 to increase glucose uptake can increase effector T-cell proliferation 47, CD8+ memory T cells utilize lipid oxidation and or this pathway by modulation of the mitochondrial lipid CPT1a can directly impact memory cell and survival 38. the metabolism of immune cells to suppress inflammation is a basic pathways, such as glycolysis, may or may not be with the glycolytic 2-deoxyglucose has been shown to suppress Given the potentially for a direct glycolytic however, the impact of this approach is not clear in the The selective of chronically stimulated cells on oxidative metabolism may allow drugs that of this pathway to the function of lymphocytes. The for the of and generation and to be to chronically stimulated lymphocytes 22. and resting cells appear to this potentially due to their ability to stress or ability to metabolically and pathways. This approach is reviewed by Wahl et al. 23 and the that selective inhibition of even basic metabolic or pathways, that appear to be fundamental to all cells, can provide some This may on the of of cells on pathways but may provide a targeting of metabolism that promote specific metabolic pathways can provide an to target metabolism. have for that can lead to AMPK activation and T-cell responses in vivo while maintaining Tregs 40. Also, nuclear hormone such as PPARs and are that may in through modulation of lymphocyte metabolism. these topics are reviewed by et al. and Kidani and Bensinger of the of the metabolic syndrome is now clearly mediated by This topic is reviewed by et al. et and et al. inflammatory pathways, therefore, are new to treat diseases. In addition, to the metabolic stress of and other metabolic tissues can Given that metabolic therapies in obesity and generally to increase lipid it is to that at a of the effects of increased lipid oxidation may be by directly promoting oxidative metabolism in immune cells because both and Treg cells lipid oxidation when to inflammatory and effector T cells. Indeed, is a that promotes AMPK activation and can some symptoms of metabolic have shown that AMPK activation drive the balance of T cells from effectors and toward Tregs 47, and this may be a component of the of that in metabolic The field of immunometabolism has been growing and in the past It is however, an entirely new field. The links between nutrition and immune have been for many The molecular links between metabolic tissues and immune signaling pathways as well as increased understanding and appreciation of direct metabolic pathways of the immune cells themselves offers a new and to understand both normal immunity as well as immunity in metabolic studies that direct changes in lymphocyte metabolism in immunity have to to the cancer metabolism as activated lymphocytes and cancer cells can be similar metabolically. In this it is appropriate that the of cancer metabolism, Otto Warburg was also one of the first to the activation of glycolysis in leukocyte activation 3. are many that of which be to our understanding of metabolic pathways in immune cells and how immunological cells interact with cells in metabolic tissues. It now is however, that these has the potential to impact a wide range of diseases. and for and This work was by the and the and The has no of interest to
Source: Immunological Reviews
Author: Jeffrey C. Rathmell
Institution: Duke University
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Award: G2071138783
OpenAlex ID: W2005118791