bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022–03–06
eight papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Metabolic programs tailor T cell immunity in viral infection, cancer, and aging.
  2. Nicotinamide breaks effector CD8 T cell responses by targeting mTOR signaling.
  3. Could Angiotensin-II induced T-cell senescence exacerbate age-related vascular dysfunction?
  4. MTHFD2, metabolic mastermind of CD4+ T cell destiny.
  5. Creatine transport and creatine kinase activity is required for CD8+ T cell immunity.
  6. Metabolic regulation of somatic stem cells in vivo.
  7. PERK is a critical metabolic hub for immunosuppressive function in macrophages.
  8. Mineral requirements for mitochondrial function: A connection to redox balance and cellular differentiation.
  1. Cell Metab. 2022 Mar 01. pii: S1550-4131(22)00047-X. [Epub ahead of print]34(3): 378-395
    Metabolic programs tailor T cell immunity in viral infection, cancer, and aging.
    Sofie Hedlund Møller, Pei-Chun Hsueh, Yi-Ru Yu, Lianjun Zhang, Ping-Chih Ho.
      Productive T cell responses to infection and cancer rely on coordinated metabolic reprogramming and epigenetic remodeling among the immune cells. In particular, T cell effector and memory differentiation, exhaustion, and senescence/aging are tightly regulated by the metabolism-epigenetics axis. In this review, we summarize recent advances of how metabolic circuits combined with epigenetic changes dictate T cell fate decisions and shape their functional states. We also discuss how the metabolic-epigenetic axis orchestrates T cell exhaustion and explore how physiological factors, such as diet, gut microbiota, and the circadian clock, are integrated in shaping T cell epigenetic modifications and functionality. Furthermore, we summarize key features of the senescent/aged T cells and discuss how to ameliorate vaccination- and COVID-induced T cell dysfunctions by metabolic modulations. An in-depth understanding of the unexplored links between cellular metabolism and epigenetic modifications in various physiological or pathological contexts has the potential to uncover novel therapeutic strategies for fine-tuning T cell immunity.
    Keywords:  CD8; COVID; aging; epigenetic; exhaustion; immunometabolism
    DOI:  https://doi.org/10.1016/j.cmet.2022.02.003
  2. iScience. 2022 Mar 18. 25(3): 103932
    Nicotinamide breaks effector CD8 T cell responses by targeting mTOR signaling.
    Federica Agliano, Timofey A Karginov, Antoine Ménoret, Anthony Provatas, Anthony T Vella.
      Nicotinamide (NAM) shapes T cell responses but its precise molecular mechanism of action remains elusive. Here, we show that NAM impairs naive T cell effector transition but also effector T cells themselves. Although aerobic glycolysis is a hallmark of activated T cells, CD8+ T cells exposed to NAM displayed enhanced glycolysis, yet producing significantly less IFNγ. Mechanistically, NAM reduced mTORC1 activity independently of NAD+ metabolism, decreasing IFNγ translation and regulating T cell transcriptional factors critical to effector/memory fate. Finally, the role of NAM in a biomedically relevant model of lung injury was tested. Specifically, a NAM-supplemented diet reduced systemic IL-2, antigen-specific T cell clonal expansion, and effector function after inhalation of Staphylococcus aureus enterotoxin A. These findings identify NAM as a potential therapeutic supplement that uncouples glycolysis from effector cytokine production and may be a powerful treatment for diseases associated with T cell hyperactivation.
    Keywords:  Biological sciences; Immunology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2022.103932
  3. J Physiol. 2022 Mar 03.
    Could Angiotensin-II induced T-cell senescence exacerbate age-related vascular dysfunction?
    Ravinandan Venkatasubramanian, Sophia A Mahoney, Zachary S Clayton.
      
    Keywords:  T cells; aging; angiotensin II; arterial stiffness; cellular senescence; endothelial dysfunction; vascular aging
    DOI:  https://doi.org/10.1113/JP282581
  4. Sci Immunol. 2022 Mar 04. 7(69): eabo6765
    MTHFD2, metabolic mastermind of CD4+ T cell destiny.
    Victoire Gouirand, Michael D Rosenblum.
      MTHFD2 is a metabolic checkpoint of T cell fate and function.
    DOI:  https://doi.org/10.1126/sciimmunol.abo6765
  5. Cell Rep. 2022 Mar 01. pii: S2211-1247(22)00173-5. [Epub ahead of print]38(9): 110446
    Creatine transport and creatine kinase activity is required for CD8+ T cell immunity.
    Bozena Samborska, Dominic G Roy, Janane F Rahbani, Mohammed F Hussain, Eric H Ma, Russell G Jones, Lawrence Kazak.
      The factors that promote T cell expansion are not fully known. Creatine is an abundant circulating metabolite that has recently been implicated in T cell function; however, its cell-autonomous role in immune-cell function is unknown. Here, we show that creatine supports cell-intrinsic CD8+ T cell homeostasis. We further identify creatine kinase B (CKB) as the creatine kinase isoenzyme that supports these T cell properties. Loss of the creatine transporter (Slc6a8) or Ckb results in compromised CD8+ T cell expansion in response to infection without influencing adenylate energy charge. Rather, loss of Slc6a8 or Ckb disrupts naive T cell homeostasis and weakens TCR-mediated activation of mechanistic target of rapamycin complex 1 (mTORC1) signaling required for CD8+ T cell expansion. These data demonstrate a cell-intrinsic role for creatine transport and creatine transphosphorylation, independent of their effects on global cellular energy charge, in supporting CD8+ T cell homeostasis and effector function.
    Keywords:  CD8+ T cells; adoptive transfer; creatine kinase; creatine metabolism; infection
    DOI:  https://doi.org/10.1016/j.celrep.2022.110446
  6. Nat Rev Mol Cell Biol. 2022 Feb 28.
    Metabolic regulation of somatic stem cells in vivo.
    Corbin E Meacham, Andrew W DeVilbiss, Sean J Morrison.
      Metabolism has been studied mainly in cultured cells or at the level of whole tissues or whole organisms in vivo. Consequently, our understanding of metabolic heterogeneity among cells within tissues is limited, particularly when it comes to rare cells with biologically distinct properties, such as stem cells. Stem cell function, tissue regeneration and cancer suppression are all metabolically regulated, although it is not yet clear whether there are metabolic mechanisms unique to stem cells that regulate their activity and function. Recent work has, however, provided evidence that stem cells do have a metabolic signature that is distinct from that of restricted progenitors and that metabolic changes influence tissue homeostasis and regeneration. Stem cell maintenance throughout life in many tissues depends upon minimizing anabolic pathway activation and cell division. Consequently, stem cell activation by tissue injury is associated with changes in mitochondrial function, lysosome activity and lipid metabolism, potentially at the cost of eroding self-renewal potential. Stem cell metabolism is also regulated by the environment: stem cells metabolically interact with other cells in their niches and are able to sense and adapt to dietary changes. The accelerating understanding of stem cell metabolism is revealing new aspects of tissue homeostasis with the potential to promote tissue regeneration and cancer suppression.
    DOI:  https://doi.org/10.1038/s41580-022-00462-1
  7. Nat Immunol. 2022 Feb 28.
    PERK is a critical metabolic hub for immunosuppressive function in macrophages.
    Lydia N Raines, Haoxin Zhao, Yuzhu Wang, Heng-Yi Chen, Hector Gallart-Ayala, Pei-Chun Hsueh, Wei Cao, Yeojung Koh, Ana Alamonte-Loya, Pu-Ste Liu, Julijana Ivanisevic, Chan-Wang Jerry Lio, Ping-Chih Ho, Stanley Ching-Cheng Huang.
      Chronic inflammation triggers compensatory immunosuppression to stop inflammation and minimize tissue damage. Studies have demonstrated that endoplasmic reticulum (ER) stress augments the suppressive phenotypes of immune cells; however, the molecular mechanisms underpinning this process and how it links to the metabolic reprogramming of immunosuppressive macrophages remain elusive. In the present study, we report that the helper T cell 2 cytokine interleukin-4 and the tumor microenvironment increase the activity of a protein kinase RNA-like ER kinase (PERK)-signaling cascade in macrophages and promote immunosuppressive M2 activation and proliferation. Loss of PERK signaling impeded mitochondrial respiration and lipid oxidation critical for M2 macrophages. PERK activation mediated the upregulation of phosphoserine aminotransferase 1 (PSAT1) and serine biosynthesis via the downstream transcription factor ATF-4. Increased serine biosynthesis resulted in enhanced mitochondrial function and α-ketoglutarate production required for JMJD3-dependent epigenetic modification. Inhibition of PERK suppressed macrophage immunosuppressive activity and could enhance the efficacy of immune checkpoint programmed cell death protein 1 inhibition in melanoma. Our findings delineate a previously undescribed connection between PERK signaling and PSAT1-mediated serine metabolism critical for promoting immunosuppressive function in M2 macrophages.
    DOI:  https://doi.org/10.1038/s41590-022-01145-x
  8. Free Radic Biol Med. 2022 Feb 23. pii: S0891-5849(22)00075-2. [Epub ahead of print]
    Mineral requirements for mitochondrial function: A connection to redox balance and cellular differentiation.
    David W Killilea, Alison N Killilea.
      Professor Bruce Ames demonstrated that nutritional recommendations should be adjusted in order to 'tune-up' metabolism and reduce mitochondria decay, a hallmark of aging and many disease processes. A major subset of tunable nutrients are the minerals, which despite being integral to every aspect of metabolism are often deficient in the typical Western diet. Mitochondria are particularly rich in minerals, where they function as essential cofactors for mitochondrial physiology and overall cellular health. Yet substantial knowledge gaps remain in our understanding of the form and function of these minerals needed for metabolic harmony. Some of the minerals have known activities in the mitochondria but with incomplete regulatory detail, whereas other minerals have no established mitochondrial function at all. A comprehensive metallome of the mitochondria is needed to fully understand the patterns and relationships of minerals within metabolic processes and cellular development. This brief overview serves to highlight the current progress towards understanding mineral homeostasis in the mitochondria and to encourage more research activity in key areas. Future work may likely reveal that adjusting the amounts of specific nutritional minerals has longevity benefits for human health.
    Keywords:  Differentiation; Metals; Minerals; Mitochondria; Redox
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.02.022
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:17.