Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch
TL;DR: CD8+ memory T cells have an Akt-dependent 'imprinted' glycolytic potential that is required for efficient immediate-early IFN-γ recall responses.
Abstract: Antigen-experienced memory T cells acquire effector function with innate-like kinetics; however, the metabolic requirements of these cells are unknown. Here we show that rapid interferon-γ (IFN-γ) production of effector memory (EM) CD8(+) T cells, activated through stimulation mediated by the T cell antigen receptor (TCR) and the costimulatory receptor CD28 or through cognate interactions, was linked to increased glycolytic flux. EM CD8(+) T cells exhibited more glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity at early time points, before proliferation commenced, than did naive cells activated under similar conditions. CD28 signaling via the serine-threonine kinase Akt and the metabolic-checkpoint kinase mTORC2 was needed to sustain TCR-mediated immediate-early glycolysis. Unlike glycolysis in proliferating cells, immediate-early glycolysis in memory CD8(+) T cells was rapamycin insensitive. Thus, CD8(+) memory T cells have an Akt-dependent 'imprinted' glycolytic potential that is required for efficient immediate-early IFN-γ recall responses.
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TL;DR: A brief refresher course on six of the major metabolic pathways involved in immunometabolism is provided, giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response.
Abstract: Immunometabolism is emerging an important area of immunological research, but for many immunologists the complexity of the field can be daunting. Here, the authors provide an overview of six key metabolic pathways that occur in immune cells and explain what is known (and what is still to be uncovered) concerning their effects on immune cell function. In recent years a substantial number of findings have been made in the area of immunometabolism, by which we mean the changes in intracellular metabolic pathways in immune cells that alter their function. Here, we provide a brief refresher course on six of the major metabolic pathways involved (specifically, glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism), giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response. What is emerging is a complex interplay between metabolic reprogramming and immunity, which is providing an extra dimension to our understanding of the immune system in health and disease.
1,857 citations
TL;DR: New metabolic checkpoints for T cell activity are uncovered and it is demonstrated that metabolic reprogramming of tumor-reactive T cells can enhance anti-tumor T cell responses, illuminating new forms of immunotherapy.
980 citations
Cites background from "Rapid effector function of memory C..."
...…enzymesmay also serve direct roles in regulating effector functions in T cells because recent work showed that when glycolytic rates are low, the glyceraldehyde phosphate dehydrogenase (GAPDH) binds to and suppresses Ifng mRNA translation in T cells (Chang et al., 2013; Gubser et al., 2013)....
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TL;DR: The role of lymphocyte metabolism on immune cell development and function and the importance of “goodtenance” in immune cell function is discussed.
Abstract: Lymphocytes must adapt to a wide array of environmental stressors as part of their normal development, during which they undergo a dramatic metabolic remodeling process. Research in this area has yielded surprising findings on the roles of diverse metabolic pathways and metabolites, which have been found to regulate lymphocyte signaling and influence differentiation, function and fate. In this review, we integrate the latest findings in the field to provide an up-to-date resource on lymphocyte metabolism.
847 citations
Cites background from "Rapid effector function of memory C..."
...…T cells to sustain their glycolytic and lipogenic machinery while maintaining mitochondrial health during times of quiescence, allowing for the rapid recall ability that is characteristic of memory T cells after antigen recognition and activation (Gubser et al., 2013; van der Windt et al., 2013)....
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...…result, memory T cells have increased mitochondrial mass and greater spare respiratory capacity (SRC) compared with naive and effector T cells, which endows them with a bioenergetic advantage for survival and recall after antigen rechallenge (van der Windt et al., 2012, 2013; Gubser et al., 2013)....
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TL;DR: Current knowledge about complement’s emerging relationship with the cellular metabolism machinery is covered with a focus on the functional differences between serum-circulating versus intracellularly active complement during normal cell survival and induction of effector functions.
Abstract: The complement system is an evolutionary old and crucial component of innate immunity key to the detection and removal of invading pathogens. It was initially discovered as a liver-derived sentinel system circulating in serum, the lymph and interstitial fluids that mediates the opsonization and lytic killing of bacteria, fungi and viruses and the initiation of the general inflammatory responses. Although work performed specifically in the last five decades identified complement also as a critical instructor of adaptive immunity – indicating that complement’s function is likely broader than initially anticipated - the dominant opinion among researchers and clinicians was that the key complement functions were in principle defined. However, there is now a growing realization that complement activity goes well beyond ‘classic’ immune functions and that this system is also required for normal (neuronal) development and activity and general cell and tissue integrity and homeostasis. Furthermore, the recent discovery that complement activation is not confined to the extracellular space but occurs within cells led to the surprising understanding that complement is involved in the regulation of basic processes of the cell, particularly those of metabolic nature – mostly via novel crosstalks between complement and intracellular sensor, and effector, pathways that had been overlooked because of their spatial separation. These paradigm shifts in the field led to a renaissance in complement research and provide new platforms to now better understand the molecular pathways underlying the wide-reaching effects of complement functions in immunity and beyond. In this review, we will cover the current knowledge about complement’s emerging relationship with the cellular metabolism machinery with a focus on the functional differences between serum-circulating versus intracellularly active complement during normal cell survival and induction of effector functions. We will also discuss how taking a closer look into the evolution of key complement components not only made the functional connection between complement and metabolism rather ‘predictable’ but how it may also give clues for the discovery of additional roles for complement in basic cellular processes.
795 citations
Cites background from "Rapid effector function of memory C..."
...While the underlying reasons for this are not fully understood, it seems that the production of the key inflammatory cytokine IFN-γ (thus, Th1 induction) poses an exceptionally high glycolytic demand on T cells (65, 72)....
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TL;DR: This review of immunometabolism will reference the most recent literature to cover the choices that environments impose on the metabolism and function of immune cells and highlight their consequences during homeostasis and disease.
787 citations
Cites background from "Rapid effector function of memory C..."
...GAPDH activity has been shown to regulate T cell production of IFN-g (Chang et al., 2013; Gubser et al., 2013)....
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...Memory T cells generated in vitro or in vivo cultured with acetate levels observed during these infections secreted more IFN-g and augmented glycolysis after restimulation....
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...In a separate report, CD4 T cells deficient in LDHA expression had defects in IFN-g production, which stemmed from widespread lack of acetylation of the Ifng locus (Peng et al., 2016)....
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...How this metabolic heterogeneity in tumor cells relates to intratumoral immune cell function has not been well elucidated, but exposure of NK and T cells to high concentrations of lactate impairs their activation of the transcription factor NFAT and production of the cytokine interferon gamma (IFN-g) (Brand et al., 2016)....
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...The loss ofmitochondrial function in TILs correlated with diminished expression of PPAR-gamma coactivator 1a (PGC1a) over time and a block in their proliferation and IFN-g production....
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References
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TL;DR: In this paper, the authors provide a detailed accounting of the biosynthetic requirements to construct a new cell and illustrate the importance of glycolysis in providing carbons to generate biomass.
Abstract: Warburg's observation that cancer cells exhibit a high rate of glycolysis even in the presence of oxygen (aerobic glycolysis) sparked debate over the role of glycolysis in normal and cancer cells. Although it has been established that defects in mitochondrial respiration are not the cause of cancer or aerobic glycolysis, the advantages of enhanced glycolysis in cancer remain controversial. Many cells ranging from microbes to lymphocytes use aerobic glycolysis during rapid proliferation, which suggests it may play a fundamental role in supporting cell growth. Here, we review how glycolysis contributes to the metabolic processes of dividing cells. We provide a detailed accounting of the biosynthetic requirements to construct a new cell and illustrate the importance of glycolysis in providing carbons to generate biomass. We argue that the major function of aerobic glycolysis is to maintain high levels of glycolytic intermediates to support anabolic reactions in cells, thus providing an explanation for why in...
2,251 citations
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TL;DR: It is shown here that aerobic glycolysis is specifically required for effector function in T cells but that this pathway is not necessary for proliferation or survival.
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