bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022–07–10
eight papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. [Molecular Profiles of Exhausted T Cells and Their Impact on Response to Immune Checkpoint Blockade].
  2. Phenotypic and Immunometabolic Aspects on Stem Cell Memory and Resident Memory CD8+ T Cells.
  3. Metabolic Regulation of Hematopoietic Stem Cells.
  4. Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators.
  5. Mitochondria-targeted senotherapeutic interventions.
  6. The metabolic profile of reconstituting T-cells, NK-cells, and monocytes following autologous stem cell transplantation and its impact on outcome.
  7. Mechanisms of mitochondrial respiratory adaptation.
  8. Interplay between Zn2+ Homeostasis and Mitochondrial Functions in Cardiovascular Diseases and Heart Ageing.
  1. Gan To Kagaku Ryoho. 2022 Jun;49(6): 609-614
    [Molecular Profiles of Exhausted T Cells and Their Impact on Response to Immune Checkpoint Blockade].
    Yuki Kagoya.
      T cell exhaustion is induced in the context of chronic virus infection and tumor microenvironment, in which cytotoxic T cells are repeatedly exposed to the target antigen and deprived of their effector functions. Multiple studies have already shown the significant impact of immune checkpoint molecules such as PD1 on functional properties of exhausted T cells. In addition to these signals, exhausted T cells possess distinct transcriptional and epigenetic profiles compared with conventional effector and memory T cells. Importantly, most of these features are not affected by immune checkpoint blockade, suggesting that genetic and epigenetic remodeling of T cells is an underlying molecular mechanism essential for T cell exhaustion. Moreover, it has now been evident that exhausted T cells are a heterogeneous cell population composed of distinct T cell subsets, and these functional differences profoundly affect therapeutic efficacy of cancer immunotherapy. In this review, I will discuss recent studies investigating molecular mechanisms of T cell exhaustion, including novel key molecules essentially associated with T cell exhaustion. These findings are potentially applicable to reinvigorate effector functions of exhausted T cells.
  2. Front Immunol. 2022 ;13 884148
    Phenotypic and Immunometabolic Aspects on Stem Cell Memory and Resident Memory CD8+ T Cells.
    Marco Pio La Manna, Mojtaba Shekarkar Azgomi, Bartolo Tamburini, Giusto Davide Badami, Leila Mohammadnezhad, Francesco Dieli, Nadia Caccamo.
      The immune system, smartly and surprisingly, saves the exposure of a particular pathogen in its memory and reacts to the pathogen very rapidly, preventing serious diseases. Immunologists have long been fascinated by understanding the ability to recall and respond faster and more vigorously to a pathogen, known as "memory". T-cell populations can be better described by using more sophisticated techniques to define phenotype, transcriptional and epigenetic signatures and metabolic pathways (single-cell resolution), which uncovered the heterogeneity of the memory T-compartment. Phenotype, effector functions, maintenance, and metabolic pathways help identify these different subsets. Here, we examine recent developments in the characterization of the heterogeneity of the memory T cell compartment. In particular, we focus on the emerging role of CD8+ TRM and TSCM cells, providing evidence on how their immunometabolism or modulation can play a vital role in their generation and maintenance in chronic conditions such as infections or autoimmune diseases.
    Keywords:  CD8 TRM cells; CD8 TSCM cells; differentiation; infectious diseases; metabolism
    DOI:  https://doi.org/10.3389/fimmu.2022.884148
  3. Hemasphere. 2022 Jul;6(7): e740
    Metabolic Regulation of Hematopoietic Stem Cells.
    Claudia Morganti, Nina Cabezas-Wallscheid, Keisuke Ito.
      Cellular metabolism is a key regulator of hematopoietic stem cell (HSC) maintenance. HSCs rely on anaerobic glycolysis for energy production to minimize the production of reactive oxygen species and shift toward mitochondrial oxidative phosphorylation upon differentiation. However, increasing evidence has shown that HSCs still maintain a certain level of mitochondrial activity in quiescence, and exhibit high mitochondrial membrane potential, which both support proper HSC function. Since glycolysis and the tricarboxylic acid (TCA) cycle are not directly connected in HSCs, other nutrient pathways, such as amino acid and fatty acid metabolism, generate acetyl-CoA and provide it to the TCA cycle. In this review, we discuss recent insights into the regulatory roles of cellular metabolism in HSCs. Understanding the metabolic requirements of healthy HSCs is of critical importance to the development of new therapies for hematological disorders.
    DOI:  https://doi.org/10.1097/HS9.0000000000000740
  4. Nat Commun. 2022 Jul 04. 13(1): 3854
    Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators.
    Purushotham Selvakumar, Ana I Fernández-Mariño, Nandish Khanra, Changhao He, Alice J Paquette, Bing Wang, Ruiqi Huang, Vaughn V Smider, William J Rice, Kenton J Swartz, Joel R Meyerson.
      The Kv1.3 potassium channel is expressed abundantly on activated T cells and mediates the cellular immune response. This role has made the channel a target for therapeutic immunomodulation to block its activity and suppress T cell activation. Here, we report structures of human Kv1.3 alone, with a nanobody inhibitor, and with an antibody-toxin fusion blocker. Rather than block the channel directly, four copies of the nanobody bind the tetramer's voltage sensing domains and the pore domain to induce an inactive pore conformation. In contrast, the antibody-toxin fusion docks its toxin domain at the extracellular mouth of the channel to insert a critical lysine into the pore. The lysine stabilizes an active conformation of the pore yet blocks ion permeation. This study visualizes Kv1.3 pore dynamics, defines two distinct mechanisms to suppress Kv1.3 channel activity with exogenous inhibitors, and provides a framework to aid development of emerging T cell immunotherapies.
    DOI:  https://doi.org/10.1038/s41467-022-31285-5
  5. Biogerontology. 2022 Jul 04.
    Mitochondria-targeted senotherapeutic interventions.
    Mehmet Can Atayik, Ufuk Çakatay.
      Healthy aging is the art of balancing a delicate scale. On one side of the scale, there are the factors that make life difficult with aging, and on the other side are the products of human effort against these factors. The most important factors that make the life difficult with aging are age-related disorders. Developing senotherapeutic strategies may bring effective solutions for the sufferers of age-related disorders. Mitochondrial dysfunction comes first in elucidating the pathogenesis of age-related disorders and presenting appropriate treatment options. Although it has been widely accepted that mitochondrial dysfunction is a common characteristic of cellular senescence, it still remains unclear why dysfunctional mitochondria occupy a central position in the development senescence-associated secretory phenotype (SASP) related to age-related disorders. Mitochondrial dysfunction and SASP-related disease progression are closely interlinked to weaken immunity which is a common phenomenon in aging. A group of substances known as senotherapeutics targeted to senescent cells can be classified into two main groups: senolytics (kill senescent cells) and senomorphics/senostatics (suppress their SASP secretions) in order to extend health lifespan and potentially lifespan. As mitochondria are also closely related to the survival of senescent cells, using either mitochondria-targeted senolytic or redox modulator senomorphic strategies may help us to solve the complex problems with the detrimental consequences of cellular senescence. Killing of senescent cells and/or ameliorate their SASP-related negative effects are currently considered to be effective mitochondria-directed gerotherapeutic approaches for fighting against age-related disorders.
    Keywords:  Aging; Mitochondria; Senescence; Senotherapeutics
    DOI:  https://doi.org/10.1007/s10522-022-09973-y
  6. Sci Rep. 2022 Jul 06. 12(1): 11406
    The metabolic profile of reconstituting T-cells, NK-cells, and monocytes following autologous stem cell transplantation and its impact on outcome.
    Silja Richter, Martin Böttcher, Simon Völkl, Andreas Mackensen, Evelyn Ullrich, Benedikt Jacobs, Dimitrios Mougiakakos.
      Previous studies indicated a role of the reconstituting immune system for disease outcome upon high-dose chemotherapy (HDCT) and autologous stem cell transplantation (auto-SCT) in multiple myeloma (MM) and lymphoma patients. Since immune cell metabolism and function are closely interconnected, we used flow-cytometry techniques to analyze key components and functions of the metabolic machinery in reconstituting immune cells upon HDCT/auto-SCT. We observed increased proliferative activity and an upregulation of the glycolytic and fatty acid oxidation (FAO) machinery in immune cells during engraftment. Metabolic activation was more pronounced in T-cells of advanced differentiation stages, in CD56bright NK-cells, and CD14++CD16+ intermediate monocytes. Next, we investigated a potential correlation between the immune cells' metabolic profile and early progression or relapse in lymphoma patients within the first twelve months following auto-SCT. Here, persistently increased metabolic parameters correlated with a rather poor disease course. Taken together, reconstituting immune cells display an upregulated bioenergetic machinery following auto-SCT. Interestingly, a persistently enhanced metabolic immune cell phenotype correlated with reduced PFS. However, it remains to be elucidated, if the clinical data can be confirmed within a larger set of patients and if residual malignant cells not detected by conventional means possibly caused the metabolic activation.
    DOI:  https://doi.org/10.1038/s41598-022-15136-3
  7. Nat Rev Mol Cell Biol. 2022 Jul 08.
    Mechanisms of mitochondrial respiratory adaptation.
    Christopher F Bennett, Pedro Latorre-Muro, Pere Puigserver.
      Mitochondrial energetic adaptations encompass a plethora of conserved processes that maintain cell and organismal fitness and survival in the changing environment by adjusting the respiratory capacity of mitochondria. These mitochondrial responses are governed by general principles of regulatory biology exemplified by changes in gene expression, protein translation, protein complex formation, transmembrane transport, enzymatic activities and metabolite levels. These changes can promote mitochondrial biogenesis and membrane dynamics that in turn support mitochondrial respiration. The main regulatory components of mitochondrial energetic adaptation include: the transcription coactivator peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC1α) and associated transcription factors; mTOR and endoplasmic reticulum stress signalling; TOM70-dependent mitochondrial protein import; the cristae remodelling factors, including mitochondrial contact site and cristae organizing system (MICOS) and OPA1; lipid remodelling; and the assembly and metabolite-dependent regulation of respiratory complexes. These adaptive molecular and structural mechanisms increase respiration to maintain basic processes specific to cell types and tissues. Failure to execute these regulatory responses causes cell damage and inflammation or senescence, compromising cell survival and the ability to adapt to energetically demanding conditions. Thus, mitochondrial adaptive cellular processes are important for physiological responses, including to nutrient availability, temperature and physical activity, and their failure leads to diseases associated with mitochondrial dysfunction such as metabolic and age-associated diseases and cancer.
    DOI:  https://doi.org/10.1038/s41580-022-00506-6
  8. Int J Mol Sci. 2022 Jun 21. pii: 6890. [Epub ahead of print]23(13):
    Interplay between Zn2+ Homeostasis and Mitochondrial Functions in Cardiovascular Diseases and Heart Ageing.
    Siarhei A Dabravolski, Nikolay K Sadykhov, Andrey G Kartuesov, Evgeny E Borisov, Vasily N Sukhorukov, Alexander N Orekhov.
      Zinc plays an important role in cardiomyocytes, where it exists in bound and histochemically reactive labile Zn2+ forms. Although Zn2+ concentration is under tight control through several Zn2+-transporters, its concentration and intracellular distribution may vary during normal cardiac function and pathological conditions, when the protein levels and efficacy of Zn2+ transporters can lead to zinc re-distribution among organelles in cardiomyocytes. Such dysregulation of cellular Zn2+ homeostasis leads to mitochondrial and ER stresses, and interrupts normal ER/mitochondria cross-talk and mitophagy, which subsequently, result in increased ROS production and dysregulated metabolic function. Besides cardiac structural and functional defects, insufficient Zn2+ supply was associated with heart development abnormalities, induction and progression of cardiovascular diseases, resulting in accelerated cardiac ageing. In the present review, we summarize the recently identified connections between cellular and mitochondrial Zn2+ homeostasis, ER stress and mitophagy in heart development, excitation-contraction coupling, heart failure and ischemia/reperfusion injury. Additionally, we discuss the role of Zn2+ in accelerated heart ageing and ageing-associated rise of mitochondrial ROS and cardiomyocyte dysfunction.
    Keywords:  ER stress; ageing; cardiovascular disease; mitophagy; zinc homeostasis
    DOI:  https://doi.org/10.3390/ijms23136890
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