bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023‒02‒12
fourteen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research
  1. The Role of Pyruvate Metabolism in Mitochondrial Quality Control and Inflammation.
  2. Role of FABP5 in T Cell Lipid Metabolism and Function in the Tumor Microenvironment.
  3. Manipulation of metabolic pathways to promote stem-like and memory T cell phenotypes for immunotherapy.
  4. CTCF mediates CD8+ effector differentiation through dynamic redistribution and genomic reorganization.
  5. Functional Overlap of Inborn Errors of Immunity and Metabolism Genes Define T Cell Immunometabolic Vulnerabilities.
  6. TET2 guards against unchecked BATF3-induced CAR T cell expansion.
  7. You can't live forever - but perhaps your T cells can.
  8. Salty Treg cells get out of balance.
  9. NOX2 and NOX4 control mitochondrial function in chronic myeloid leukaemia.
  10. Neoadjuvant chemotherapy modulates exhaustion of T cells in breast cancer patients.
  11. Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs.
  12. Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
  13. T Cell Energy Metabolism Is a Target of Glucocorticoids in Mice, Healthy Humans, and MS Patients.
  14. The potential role of short chain fatty acids improving ex vivo T and CAR-T cell fitness and expansion for cancer immunotherapies.
  1. Mol Cells. 2023 Feb 09.
    The Role of Pyruvate Metabolism in Mitochondrial Quality Control and Inflammation.
    Min-Ji Kim, Hoyul Lee, Dipanjan Chanda, Themis Thoudam, Hyeon-Ji Kang, Robert A Harris, In-Kyu Lee.
      Pyruvate metabolism, a key pathway in glycolysis and oxidative phosphorylation, is crucial for energy homeostasis and mitochondrial quality control (MQC), including fusion/fission dynamics and mitophagy. Alterations in pyruvate flux and MQC are associated with reactive oxygen species accumulation and Ca2+ flux into the mitochondria, which can induce mitochondrial ultrastructural changes, mitochondrial dysfunction and metabolic dysregulation. Perturbations in MQC are emerging as a central mechanism for the pathogenesis of various metabolic diseases, such as neurodegenerative diseases, diabetes and insulin resistance-related diseases. Mitochondrial Ca2+ regulates the pyruvate dehydrogenase complex (PDC), which is central to pyruvate metabolism, by promoting its dephosphorylation. Increase of pyruvate dehydrogenase kinase (PDK) is associated with perturbation of mitochondria-associated membranes (MAMs) function and Ca2+ flux. Pyruvate metabolism also plays an important role in immune cell activation and function, dysregulation of which also leads to insulin resistance and inflammatory disease. Pyruvate metabolism affects macrophage polarization, mitochondrial dynamics and MAM formation, which are critical in determining macrophage function and immune response. MAMs and MQCs have also been intensively studied in macrophage and T cell immunity. Metabolic reprogramming connected with pyruvate metabolism, mitochondrial dynamics and MAM formation are important to macrophages polarization (M1/M2) and function. T cell differentiation is also directly linked to pyruvate metabolism, with inhibition of pyruvate oxidation by PDKs promoting proinflammatory T cell polarization. This article provides a brief review on the emerging role of pyruvate metabolism in MQC and MAM function, and how dysfunction in these processes leads to metabolic and inflammatory diseases.
    Keywords:  T cell; macrophage; mitochondria quality control; mitochondria-associated membranes; pyruvate dehydrogenase complex; pyruvate dehydrogenase kinase
    DOI:  https://doi.org/10.14348/molcells.2023.2128
  2. Cancers (Basel). 2023 Jan 20. pii: 657. [Epub ahead of print]15(3):
    Role of FABP5 in T Cell Lipid Metabolism and Function in the Tumor Microenvironment.
    Rong Jin, Jiaqing Hao, Jianyu Yu, Pingzhang Wang, Edward R Sauter, Bing Li.
      To evade immune surveillance, tumors develop a hostile microenvironment that inhibits anti-tumor immunity. Recent immunotherapy breakthroughs that target the reinvigoration of tumor-infiltrating T lymphocytes (TIL) have led to unprecedented success in treating some cancers that are resistant to conventional therapy, suggesting that T cells play a pivotal role in anti-tumor immunity. In the hostile tumor microenvironment (TME), activated T cells are known to mainly rely on aerobic glycolysis to facilitate their proliferation and anti-tumor function. However, TILs usually exhibit an exhausted phenotype and impaired anti-tumor activity due to the limited availability of key nutrients (e.g., glucose) in the TME. Given that different T cell subsets have unique metabolic pathways which determine their effector function, this review introduces our current understanding of T cell development, activation signals and metabolic pathways. Moreover, emerging evidence suggests that fatty acid binding protein 5 (FABP5) expression in T cells regulates T cell lipid metabolism and function. We highlight how FABP5 regulates fatty acid uptake and oxidation, thus shaping the survival and function of different T cell subsets in the TME.
    Keywords:  FABP5; T cells; immunotherapy; lipid metabolism; obesity; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers15030657
  3. Front Immunol. 2022 ;13 1061411
    Manipulation of metabolic pathways to promote stem-like and memory T cell phenotypes for immunotherapy.
    Michael D Claiborne.
      Utilizing the immune system's capacity to recognize and kill tumor cells has revolutionized cancer therapy in recent decades. Phenotypic study of antitumor T cells supports the principle that superior tumor control is achieved by cells with more long-lived memory or stem-like properties as compared to terminally differentiated effector cells. In this Mini-Review, we explore recent advances in profiling the different metabolic programs that both generate and define subsets of memory T cells. We additionally discuss new experimental approaches that aim to maximize the durability and sustained antitumor response associated with memory T cells within the unique immunosuppressive conditions of the tumor microenvironment, such as engineered attempts to overcome hypoxia-induced changes in mitochondrial function, the inhibitory effects of tumor metabolites, and exploitation of more recently-defined metabolic pathways controlling T cell memory fate such as glycogen metabolism.
    Keywords:  CAR T cancer therapy; T cell memory; adoptive cell immunotherapy; immunology; metabolism; tumor immunology
    DOI:  https://doi.org/10.3389/fimmu.2022.1061411
  4. J Exp Med. 2023 Apr 03. pii: e20221288. [Epub ahead of print]220(4):
    CTCF mediates CD8+ effector differentiation through dynamic redistribution and genomic reorganization.
    Jia Liu, Shaoqi Zhu, Wei Hu, Xin Zhao, Qiang Shan, Weiqun Peng, Hai-Hui Xue.
      Differentiation of effector CD8+ T cells is instructed by stably and dynamically expressed transcription regulators. Here we show that naive-to-effector differentiation was accompanied by dynamic CTCF redistribution and extensive chromatin architectural changes. Upon CD8+ T cell activation, CTCF acquired de novo binding sites and anchored novel chromatin interactions, and these changes were associated with increased chromatin accessibility and elevated expression of cytotoxic program genes including Tbx21, Ifng, and Klrg1. CTCF was also evicted from its ex-binding sites in naive state, with concomitantly reduced chromatin interactions in effector cells, as observed at memory precursor-associated genes including Il7r, Sell, and Tcf7. Genetic ablation of CTCF indeed diminished cytotoxic gene expression, but paradoxically elevated expression of memory precursor genes. Comparative Hi-C analysis revealed that key memory precursor genes were harbored within insulated neighborhoods demarcated by constitutive CTCF binding, and their induction was likely due to disrupted CTCF-dependent insulation. CTCF thus promotes cytotoxic effector differentiation by integrating local chromatin accessibility control and higher-order genomic reorganization.
    DOI:  https://doi.org/10.1084/jem.20221288
  5. bioRxiv. 2023 Jan 24. pii: 2023.01.24.525419. [Epub ahead of print]
    Functional Overlap of Inborn Errors of Immunity and Metabolism Genes Define T Cell Immunometabolic Vulnerabilities.
    Andrew R Patterson, Gabriel A Needle, Ayaka Sugiura, Channing Chi, KayLee K Steiner, Emilie L Fisher, Gabriella L Robertson, Caroline Bodnya, Janet G Markle, Vivian Gama, Jeffrey C Rathmell.
      Inborn Errors of Metabolism (IEM) and Immunity (IEI) are Mendelian diseases in which complex phenotypes and patient rarity can limit clinical annotations. Few genes are assigned to both IEM and IEI, but immunometabolic demands suggest functional overlap is underestimated. We applied CRISPR screens to test IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable crossover. Analysis of IEM showed N-linked glycosylation and the de novo hexosamine synthesis enzyme, Gfpt1 , are critical for T cell expansion and function. Interestingly, Gfpt1 -deficient T H 1 cells were more affected than T H 17 cells, which had increased Nagk for salvage UDP-GlcNAc synthesis. Screening IEI genes showed the transcription factor Bcl11b promotes CD4 + T cell mitochondrial activity and Mcl1 expression necessary to prevent metabolic stress. These data illustrate a high degree of functional overlap of IEM and IEI genes and point to potential immunometabolic mechanisms for a previously unappreciated set of these disorders.HIGHLIGHTS: Inborn errors of immunity and metabolism have greater overlap than previously known Gfpt1 deficiency causes an IEM but also selectively regulates T cell subset fate Loss of Bcl11b causes a T cell deficiency IEI but also harms mitochondrial function Many IEM may have immune defects and IEI may be driven by metabolic mechanisms.
    DOI:  https://doi.org/10.1101/2023.01.24.525419
  6. Nature. 2023 Feb 08.
    TET2 guards against unchecked BATF3-induced CAR T cell expansion.
    Nayan Jain, Zeguo Zhao, Judith Feucht, Richard Koche, Archana Iyer, Anton Dobrin, Jorge Mansilla-Soto, Julie Yang, Yingqian Zhan, Michael Lopez, Gertrude Gunset, Michel Sadelain.
      Further advances in cell engineering are needed to increase the efficacy of chimeric antigen receptor (CAR) and other T cell-based therapies1-5. As T cell differentiation and functional states are associated with distinct epigenetic profiles6,7, we hypothesized that epigenetic programming may provide a means to improve CAR T cell performance. Targeting the gene that encodes the epigenetic regulator ten-eleven translocation 2 (TET2)8 presents an interesting opportunity as its loss may enhance T cell memory9,10, albeit not cause malignancy9,11,12. Here we show that disruption of TET2 enhances T cell-mediated tumour rejection in leukaemia and prostate cancer models. However, loss of TET2 also enables antigen-independent CAR T cell clonal expansions that may eventually result in prominent systemic tissue infiltration. These clonal proliferations require biallelic TET2 disruption and sustained expression of the AP-1 factor BATF3 to drive a MYC-dependent proliferative program. This proliferative state is associated with reduced effector function that differs from both canonical T cell memory13,14 and exhaustion15,16 states, and is prone to the acquisition of secondary somatic mutations, establishing TET2 as a guardian against BATF3-induced CAR T cell proliferation and ensuing genomic instability. Our findings illustrate the potential of epigenetic programming to enhance T cell immunity but highlight the risk of unleashing unchecked proliferative responses.
    DOI:  https://doi.org/10.1038/s41586-022-05692-z
  7. Nat Rev Immunol. 2023 Feb 10.
    You can't live forever - but perhaps your T cells can.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-023-00845-1
  8. Cell Metab. 2023 Feb 07. pii: S1550-4131(23)00008-6. [Epub ahead of print]35(2): 228-230
    Salty Treg cells get out of balance.
    Iosif Papafragkos, Panayotis Verginis.
      Although metabolic rewiring of Treg cells constitutes a hallmark in autoimmune diseases, extrinsic and intrinsic mechanisms that imprint on this re-programming remain poorly understood. In this issue of Cell Metabolism, Côrte-Real and colleagues demonstrate that high salt exposure disturbs the mitochondrial respiration in Treg cells, promoting a pro-inflammatory phenotype, loss of function, and associated breakdown of self-tolerance.
    DOI:  https://doi.org/10.1016/j.cmet.2023.01.008
  9. Free Radic Biol Med. 2023 Feb 08. pii: S0891-5849(23)00054-0. [Epub ahead of print]
    NOX2 and NOX4 control mitochondrial function in chronic myeloid leukaemia.
    Marta Romo-González, Carla Ijurko, María Teresa Alonso, Marta Gómez de Cedrón, Ana Ramirez de Molina, María Eugenia Soriano, Ángel Hernández-Hernández.
      Cancer cells are characterised by an elevated metabolic plasticity and enhanced production of reactive oxygen species (ROS), two features acknowledged as hallmarks in cancer, with a high translational potential to the therapeutic setting. These aspects, that have been traditionally studied separately, are in fact intimately intermingled. As part of their transforming activity, some oncogenes stimulate rewiring of metabolic processes, whilst simultaneously promoting increased production of intracellular ROS. In this scenario the latest discoveries suggest the relevance of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) to connect ROS production and metabolic control. Here we have analysed the relevance of NOX2 and NOX4 in the regulation of metabolism in chronic myeloid leukaemia (CML), a neoplasia driven by the expression of the breakpoint cluster region-Abelson fusion oncogene (BCR-ABL). Silencing of NOX2 enhances glycolysis and oxidative phosphorylation rates, together with an enhanced production of mitochondrial ROS and a decrease in mitochondrial DNA copy number, which reflects mitochondrial dysfunction. NOX4 expression was upregulated upon NOX2 silencing, and this was required to alter mitochondrial function. Our results support the relevance of NOX2 to regulate metabolism-related signalling pathways downstream of BCR-ABL. Overall we show that NOX2, through the regulation of NOX4 expression, controls metabolism and mitochondrial function in CML cells. This notion was confirmed by transcriptomic analyses, that strongly relate both NOX isoforms with metabolism regulation in CML.
    Keywords:  Chronic myeloid leukaemia; Metabolism; Mitochondria; NOX2; NOX4; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.02.005
  10. PLoS One. 2023 ;18(2): e0280851
    Neoadjuvant chemotherapy modulates exhaustion of T cells in breast cancer patients.
    Ivon Johanna Rodríguez, David A Bernal-Estévez, Manuela Llano-León, Carlos Eduardo Bonilla, Carlos Alberto Parra-López.
      Breast cancer is the leading cause of cancer deaths in women worldwide. It has been observed that the incidence of breast cancer increases linearly with age after 45, which suggest a link between cancer, aging, and senescence. A growing body of evidence indicates that the immunosuppressive tumor network in breast cancer patients can lead to T-cell exhaustion and senescence. Cytotoxic chemotherapy is a common treatment for many cancers, and it is hypothesized that its efficacy may be related to immune activation. However, the effects of neoadjuvant chemotherapy on T-cell dysfunction in breast cancer patients are not fully understood. This study aimed to evaluate the impact of neoadjuvant chemotherapy on the expression of exhaustion and senescence markers in T cells in women with breast cancer. Our results showed that T cells from breast cancer patients have a reduced ability to respond to stimulation in-vitro and an increased expression of senescence and exhaustion-associated markers, such as TIM-3, LAG3, and CD57. Furthermore, we found that neoadjuvant chemotherapy has an immunomodulatory effect and reduces the expression of exhaustion markers. Our observations of the immune phenotype of T cells during neoadjuvant chemotherapy treatment highlight its ability to stimulate the immune system against cancer. Therefore, monitoring the response of T cells during chemotherapy may enable early prediction of clinical response.
    DOI:  https://doi.org/10.1371/journal.pone.0280851
  11. Cell Metab. 2023 Feb 07. pii: S1550-4131(23)00009-8. [Epub ahead of print]35(2): 299-315.e8
    Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs.
    Beatriz F Côrte-Real, Ibrahim Hamad, Rebeca Arroyo Hornero, Sabrina Geisberger, Joris Roels, Lauren Van Zeebroeck, Aleksandra Dyczko, Marike W van Gisbergen, Henry Kurniawan, Allon Wagner, Nir Yosef, Susanne N Y Weiss, Klaus G Schmetterer, Agnes Schröder, Luka Krampert, Stefanie Haase, Hendrik Bartolomaeus, Niels Hellings, Yvan Saeys, Ludwig J Dubois, Dirk Brenner, Stefan Kempa, David A Hafler, Johannes Stegbauer, Ralf A Linker, Jonathan Jantsch, Dominik N Müller, Markus Kleinewietfeld.
      FOXP3+ regulatory T cells (Tregs) are central for peripheral tolerance, and their deregulation is associated with autoimmunity. Dysfunctional autoimmune Tregs display pro-inflammatory features and altered mitochondrial metabolism, but contributing factors remain elusive. High salt (HS) has been identified to alter immune function and to promote autoimmunity. By investigating longitudinal transcriptional changes of human Tregs, we identified that HS induces metabolic reprogramming, recapitulating features of autoimmune Tregs. Mechanistically, extracellular HS raises intracellular Na+, perturbing mitochondrial respiration by interfering with the electron transport chain (ETC). Metabolic disturbance by a temporary HS encounter or complex III blockade rapidly induces a pro-inflammatory signature and FOXP3 downregulation, leading to long-term dysfunction in vitro and in vivo. The HS-induced effect could be reversed by inhibition of mitochondrial Na+/Ca2+ exchanger (NCLX). Our results indicate that salt could contribute to metabolic reprogramming and that short-term HS encounter perturb metabolic fitness and long-term function of human Tregs with important implications for autoimmunity.
    Keywords:  FOXP3; autoimmunity; high salt; mitochondrial respiration; regulatory T cells
    DOI:  https://doi.org/10.1016/j.cmet.2023.01.009
  12. Int J Mol Sci. 2023 Jan 19. pii: 2010. [Epub ahead of print]24(3):
    Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
    Jessica Maya, Sabrina M Leddy, C Gunnar Gottschalk, Daniel L Peterson, Maureen R Hanson.
      Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling multisystem illness in which individuals are plagued with fatigue, inflammatory symptoms, cognitive dysfunction, and the hallmark symptom, post-exertional malaise. While the cause of this disease remains unknown, there is evidence of a potential infectious component that, along with patient symptoms and common onsets of the disease, implicates immune system dysfunction. To further our understanding of the state of ME/CFS lymphocytes, we characterized the role of fatty acids in isolated Natural Killer cells, CD4+ T cells, and CD8+ T cells in circulation and after overnight stimulation, through implicit perturbations to fatty acid oxidation. We examined samples obtained from at least 8 and as many as 20 subjects for immune cell fatty acid characterization in a variety of experiments and found that all three isolated cell types increased their utilization of lipids and levels of pertinent proteins involved in this metabolic pathway in ME/CFS samples, particularly during higher energy demands and activation. In T cells, we characterized the cell populations contributing to these metabolic shifts, which included CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells. We also discovered that patients with ME/CFS and healthy control samples had significant correlations between measurements of CD4+ T cell fatty acid metabolism and demographic data. These findings provide support for metabolic dysfunction in ME/CFS immune cells. We further hypothesize about the consequences that these altered fuel dependencies may have on T and NK cell effector function, which may shed light on the illness's mechanism of action.
    Keywords:  Natural Killer cells; T cells; beta-oxidation; chronic fatigue syndrome; fatty acid oxidation; immunometabolism; myalgic encephalomyelitis
    DOI:  https://doi.org/10.3390/ijms24032010
  13. Cells. 2023 Jan 30. pii: 450. [Epub ahead of print]12(3):
    T Cell Energy Metabolism Is a Target of Glucocorticoids in Mice, Healthy Humans, and MS Patients.
    Leonie Meyer-Heemsoth, Katja Mitschke, Jasmina Bier, Konstantin Schütz, Andreas Villunger, Tobias J Legler, Martin S Weber, Fred Lühder, Holger M Reichardt.
      Glucocorticoids (GCs) are used to treat inflammatory disorders such as multiple sclerosis (MS) by exerting prominent activities in T cells including apoptosis induction and suppression of cytokine production. However, little is known about their impact on energy metabolism, although it is widely accepted that this process is a critical rheostat of T cell activity. We thus tested the hypothesis that GCs control genes and processes involved in nutrient transport and glycolysis. Our experiments revealed that escalating doses of dexamethasone (Dex) repressed energy metabolism in murine and human primary T cells. This effect was mediated by the GC receptor and unrelated to both apoptosis induction and Stat1 activity. In contrast, treatment of human T cells with rapamycin abolished the repression of metabolic gene expression by Dex, unveiling mTOR as a critical target of GC action. A similar phenomenon was observed in MS patients after intravenous methylprednisolon (IVMP) pulse therapy. The expression of metabolic genes was reduced in the peripheral blood T cells of most patients 24 h after GC treatment, an effect that correlated with disease activity. Collectively, our results establish the regulation of T cell energy metabolism by GCs as a new immunomodulatory principle.
    Keywords:  T cells; glucocorticoids; metabolism; multiple sclerosis
    DOI:  https://doi.org/10.3390/cells12030450
  14. Front Immunol. 2023 ;14 1083303
    The potential role of short chain fatty acids improving ex vivo T and CAR-T cell fitness and expansion for cancer immunotherapies.
    Adrián González-Brito, Mireia Uribe-Herranz.
      Adoptive cell therapies, like tumor-infiltrating lymphocytes or chimeric antigen receptor T cells, have become an important immunotherapeutic approach against cancer. One of the main struggles of T cell immunotherapies is how to obtain the most effective T cell phenotype, persistence, and differentiation potential to infuse into patients. Adjusting the T cell ex vivo cell culture conditions is a key factor to increase and improve the efficacy of cellular immunotherapies. In this review, we have summarized the ex vivo impact of short chain fatty acids, a group of gut microbiota derived metabolites, on T cell culture and expansion for immunotherapies. There is a complex gut microbiota-immune system interaction that can affect antitumor immunotherapy efficacy. Indeed, gut microbiota derived metabolites can modulate different biological functions in the immune system local and systemically.
    Keywords:  T cells; car-t; ex vivo; gut microbiota; immunotherapy; short chain fatty acids
    DOI:  https://doi.org/10.3389/fimmu.2023.1083303
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