bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022–03–13
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Metabolic dynamics instructs CD8+ T cell differentiation and functions.
  2. Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses.
  3. Iron Supplementation Delays Aging and Extends Cellular Lifespan through Potentiation of Mitochondrial Function.
  4. Metabolic Regulation of Stem Cells in Aging.
  5. Strategies for Manipulating T Cells in Cancer Immunotherapy.
  6. Tryptophan depletion results in tryptophan-to-phenylalanine substitutants.
  7. The Extracellular ATP Receptor P2RX7 Imprints a Promemory Transcriptional Signature in Effector CD8+ T Cells.
  8. Mitochondrial Proteins as Source of Cancer Neoantigens.
  9. CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging.
  10. Magnesium for T cells: strong to the finish!
  1. Eur J Immunol. 2022 Mar 06.
    Metabolic dynamics instructs CD8+ T cell differentiation and functions.
    Alessio Bevilacqua, Zhiyu Li, Ping-Chih Ho.
      Cytotoxic CD8+ T cells are a key element of the adaptative immune system to protect the organism against infections and malignant cells. During their activation and response T cells undergo different metabolic pathways to support their energetic needs according to their localization and function. However, it has also been recently appreciated that this metabolic reprogramming also directly supports T cells lineage differentiation. Accordingly, metabolic deficiencies and prolonged stress exposure can impact T cell differentiation and skew them into exhausted state. Here, we review how metabolism defines CD8+ T cells differentiation and function. Moreover, we cover the principal metabolic dysregulation that promotes the exhausted phenotype under tumor or chronic virus condition. Finally, we summarize recent strategies to reprogram impaired metabolic pathways to promote CD8+ T cells effector function and survival. This article is protected by copyright. All rights reserved.
    Keywords:  T cell differentiation; T cell exhaustion; T cells; infection; metabolism
    DOI:  https://doi.org/10.1002/eji.202149486
  2. Front Immunol. 2022 ;13 837669
    Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses.
    David Bargiela, Pedro P Cunha, Pedro Veliça, Iosifina P Foskolou, Laura Barbieri, Helene Rundqvist, Randall S Johnson.
      Targeting T cell metabolism is an established method of immunomodulation. Following activation, T cells engage distinct metabolic programs leading to the uptake and processing of nutrients that determine cell proliferation and differentiation. Redirection of T cell fate by modulation of these metabolic programs has been shown to boost or suppress immune responses in vitro and in vivo. Using publicly available T cell transcriptomic and proteomic datasets we identified vitamin B6-dependent transaminases as key metabolic enzymes driving T cell activation and differentiation. Inhibition of vitamin B6 metabolism using the pyridoxal 5'-phosphate (PLP) inhibitor, aminoxyacetic acid (AOA), suppresses CD8+ T cell proliferation and effector differentiation in a dose-dependent manner. We show that pyridoxal phosphate phosphatase (PDXP), a negative regulator of intracellular vitamin B6 levels, is under the control of the hypoxia-inducible transcription factor (HIF1), a central driver of T cell metabolism. Furthermore, by adoptive transfer of CD8 T cells into a C57BL/6 mouse melanoma model, we demonstrate the requirement for vitamin B6-dependent enzyme activity in mediating effective anti-tumor responses. Our findings show that vitamin B6 metabolism is required for CD8+ T cell proliferation and effector differentiation in vitro and in vivo. Targeting vitamin B6 metabolism may therefore serve as an immunodulatory strategy to improve anti-tumor immunotherapy.
    Keywords:  CD8+ lymphocytes; hypoxia; immunotherapy; metabolism; vitamin B6
    DOI:  https://doi.org/10.3389/fimmu.2022.837669
  3. Cells. 2022 Mar 02. pii: 862. [Epub ahead of print]11(5):
    Iron Supplementation Delays Aging and Extends Cellular Lifespan through Potentiation of Mitochondrial Function.
    Jovian Lin Jing, Trishia Cheng Yi Ning, Federica Natali, Frank Eisenhaber, Mohammad Alfatah.
      Aging is the greatest challenge to humankind worldwide. Aging is associated with a progressive loss of physiological integrity due to a decline in cellular metabolism and functions. Such metabolic changes lead to age-related diseases, thereby compromising human health for the remaining life. Thus, there is an urgent need to identify geroprotectors that regulate metabolic functions to target the aging biological processes. Nutrients are the major regulator of metabolic activities to coordinate cell growth and development. Iron is an important nutrient involved in several biological functions, including metabolism. In this study using yeast as an aging model organism, we show that iron supplementation delays aging and increases the cellular lifespan. To determine how iron supplementation increases lifespan, we performed a gene expression analysis of mitochondria, the main cellular hub of iron utilization. Quantitative analysis of gene expression data reveals that iron supplementation upregulates the expression of the mitochondrial tricarboxylic acid (TCA) cycle and electron transport chain (ETC) genes. Furthermore, in agreement with the expression profiles of mitochondrial genes, ATP level is elevated by iron supplementation, which is required for increasing the cellular lifespan. To confirm, we tested the role of iron supplementation in the AMPK knockout mutant. AMPK is a highly conserved controller of mitochondrial metabolism and energy homeostasis. Remarkably, iron supplementation rescued the short lifespan of the AMPK knockout mutant and confirmed its anti-aging role through the enhancement of mitochondrial functions. Thus, our results suggest a potential therapeutic use of iron supplementation to delay aging and prolong healthspan.
    Keywords:  AMPK; Saccharomyces cerevisiae; cellular lifespan extension; chronological aging; iron; mitochondria
    DOI:  https://doi.org/10.3390/cells11050862
  4. Curr Stem Cell Rep. 2021 Jun;7(2): 72-84
    Metabolic Regulation of Stem Cells in Aging.
    Andrea Keller, Tyus Temple, Behnam Sayanjali, Maria M Mihaylova.
       Purpose of Review: From invertebrates to vertebrates, the ability to sense nutrient availability is critical for survival. Complex organisms have evolved numerous signaling pathways to sense nutrients and dietary fluctuations, which influence many cellular processes. Although both overabundance and extreme depletion of nutrients can lead to deleterious effects, dietary restriction without malnutrition can increase lifespan and promote overall health in many model organisms. In this review, we focus on age-dependent changes in stem cell metabolism and dietary interventions used to modulate stem cell function in aging.
    Recent Findings: Over the last half-century, seminal studies have illustrated that dietary restriction confers beneficial effects on longevity in many model organisms. Many researchers have now turned to dissecting the molecular mechanisms by which these diets affect aging at the cellular level. One subpopulation of cells of particular interest are adult stem cells, the most regenerative cells of the body. It is generally accepted that the regenerative capacity of stem cells declines with age, and while the metabolic requirements of each vary across tissues, the ability of dietary interventions to influence stem cell function is striking.
    Summary: In this review, we will focus primarily on how metabolism plays a role in adult stem cell homeostasis with respect to aging, with particular emphasis on intestinal stem cells while also touching on hematopoietic, skeletal muscle, and neural stem cells. We will also discuss key metabolic signaling pathways influenced by both dietary restriction and the aging process, and will examine their role in improving tissue homeostasis and lifespan. Understanding the mechanisms behind the metabolic needs of stem cells will help bridge the divide between a basic science interpretation of stem cell function and a whole-organism view of nutrition, thereby providing insight into potential dietary or therapeutic interventions.
    Keywords:  Aging; Metabolism; stem cells
    DOI:  https://doi.org/10.1007/s40778-021-00186-6
  5. Biomol Ther (Seoul). 2022 Mar 10.
    Strategies for Manipulating T Cells in Cancer Immunotherapy.
    Hyang-Mi Lee.
      T cells are attractive targets for the development of immunotherapy to treat cancer due to their biological features, capacity of cytotoxicity, and antigen-specific binding of receptors. Novel strategies that can modulate T cell functions or receptor reactivity provide effective therapies, including checkpoint inhibitor, bispecific antibody, and adoptive transfer of T cells transduced with tumor antigen-specific receptors. T cell-based therapies have presented successful pre-clinical/clinical outcomes despite their common immune-related adverse effects. Ongoing studies will allow us to advance current T cell therapies and develop innovative personalized T cell therapies. This review summarizes immunotherapeutic approaches with a focus on T cells. Anti-cancer T cell therapies are also discussed regarding their biological perspectives, efficacy, toxicity, challenges, and opportunities.
    Keywords:  Adoptive T cell transfer; Bispecific antibody; Cancer immunotherapy; Checkpoint inhibitor; Tumor-specific T cells
    DOI:  https://doi.org/10.4062/biomolther.2021.180
  6. Nature. 2022 Mar 09.
    Tryptophan depletion results in tryptophan-to-phenylalanine substitutants.
    Abhijeet Pataskar, Julien Champagne, Remco Nagel, Juliana Kenski, Maarja Laos, Justine Michaux, Hui Song Pak, Onno B Bleijerveld, Kelly Mordente, Jasmine Montenegro Navarro, Naomi Blommaert, Morten M Nielsen, Domenica Lovecchio, Everett Stone, George Georgiou, Mark C de Gooijer, Olaf van Tellingen, Maarten Altelaar, Robbie P Joosten, Anastassis Perrakis, Johanna Olweus, Michal Bassani-Sternberg, Daniel S Peeper, Reuven Agami.
      Activated T cells secrete interferon-γ, which triggers intracellular tryptophan shortage by upregulating the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme1-4. Here we show that despite tryptophan depletion, in-frame protein synthesis continues across tryptophan codons. We identified tryptophan-to-phenylalanine codon reassignment (W>F) as the major event facilitating this process, and pinpointed tryptophanyl-tRNA synthetase (WARS1) as its source. We call these W>F peptides 'substitutants' to distinguish them from genetically encoded mutants. Using large-scale proteomics analyses, we demonstrate W>F substitutants to be highly abundant in multiple cancer types. W>F substitutants were enriched in tumours relative to matching adjacent normal tissues, and were associated with increased IDO1 expression, oncogenic signalling and the tumour-immune microenvironment. Functionally, W>F substitutants can impair protein activity, but also expand the landscape of antigens presented at the cell surface to activate T cell responses. Thus, substitutants are generated by an alternative decoding mechanism with potential effects on gene function and tumour immunoreactivity.
    DOI:  https://doi.org/10.1038/s41586-022-04499-2
  7. J Immunol. 2022 Mar 09. pii: ji2100555. [Epub ahead of print]
    The Extracellular ATP Receptor P2RX7 Imprints a Promemory Transcriptional Signature in Effector CD8+ T Cells.
    Trupti Vardam-Kaur, Sarah van Dijk, Changwei Peng, Kelsey M Wanhainen, Stephen C Jameson, Henrique Borges da Silva.
      Development of CD8+ central memory T (Tcm) and resident memory T (Trm) cells, which promote immunity in the circulation and in barrier tissues, respectively, is not completely understood. Tcm and Trm cells may arise from common precursors; however, their fate-inducing signals are elusive. We found that virus-specific effector CD8+ T cells display heterogeneous expression of the extracellular ATP sensor P2RX7. P2RX7-high expression is confined, at peak effector phase, to CD62L+ memory precursors, which preferentially form Tcm cells. Among early effector CD8+ T cells, asymmetrical P2RX7 distribution correlated with distinct transcriptional signatures, with P2RX7-high cells enriched for memory and tissue residency sets. P2RX7-high early effectors preferentially form both Tcm and Trm cells. Defective Tcm and Trm cell formation in P2RX7 deficiency is significantly reverted when the transcriptional repressor Zeb2 is ablated. Mechanistically, P2RX7 negatively regulates Zeb2 expression, at least partially through TGF-β sensing in early effector CD8+ T cells. Our study indicates that unequal P2RX7 upregulation in effector CD8+ T cells is a foundational element of the early Tcm/Trm fate.
    DOI:  https://doi.org/10.4049/jimmunol.2100555
  8. Int J Mol Sci. 2022 Feb 27. pii: 2627. [Epub ahead of print]23(5):
    Mitochondrial Proteins as Source of Cancer Neoantigens.
    Gennaro Prota, Ana Victoria Lechuga-Vieco, Gennaro De Libero.
      In the past decade, anti-tumour immune responses have been successfully exploited to improve the outcome of patients with different cancers. Significant progress has been made in taking advantage of different types of T cell functions for therapeutic purposes. Despite these achievements, only a subset of patients respond favorably to immunotherapy. Therefore, there is a need of novel approaches to improve the effector functions of immune cells and to recognize the major targets of anti-tumour immunity. A major hallmark of cancer is metabolic rewiring associated with switch of mitochondrial functions. These changes are a consequence of high energy demand and increased macromolecular synthesis in cancer cells. Such adaptations in tumour cells might generate novel targets of tumour therapy, including the generation of neoantigens. Here, we review the most recent advances in research on the immune response to mitochondrial proteins in different cellular conditions.
    Keywords:  T cell response; cancer neoantigens; mitochondria; mtDNA mutations; post translational modifications
    DOI:  https://doi.org/10.3390/ijms23052627
  9. Aging Cell. 2022 Mar 08. e13589
    CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging.
    Thais R Peclat, Katie L Thompson, Gina M Warner, Claudia C S Chini, Mariana G Tarragó, Delaram Z Mazdeh, Chunlian Zhang, Jose Zavala-Solorio, Ganesh Kolumam, Yao Liang Wong, Robert L Cohen, Eduardo N Chini.
      Nicotinamide adenine dinucleotide (NAD) levels decline during aging, contributing to physical and metabolic dysfunction. The NADase CD38 plays a key role in age-related NAD decline. Whether the inhibition of CD38 increases lifespan is not known. Here, we show that the CD38 inhibitor 78c increases lifespan and healthspan of naturally aged mice. In addition to a 10% increase in median survival, 78c improved exercise performance, endurance, and metabolic function in mice. The effects of 78c were different between sexes. Our study is the first to investigate the effect of CD38 inhibition in naturally aged animals.
    Keywords:  CD38; NAD; aging; healthspan; longevity; mice; small molecule
    DOI:  https://doi.org/10.1111/acel.13589
  10. Trends Immunol. 2022 Mar 05. pii: S1471-4906(22)00043-6. [Epub ahead of print]
    Magnesium for T cells: strong to the finish!
    Santosha Vardhana, Michael L Dustin.
      'Popeye, the Sailor' cartoons taught children that eating spinach boosts strength and helps defend against bullies. Lötscher and colleagues report that dietary deficiency of magnesium ions (Mg2+), against which eating spinach is an excellent antidote, impairs the activity of a key adhesion molecule, LFA-1, and hinders the ability of CD8+ T cells to grapple with assorted bullies, such as tumors and bacteria.
    DOI:  https://doi.org/10.1016/j.it.2022.02.004
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