bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022‒02‒20
twelve papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. Immun Ageing. 2022 Feb 14. 19(1): 9
      BACKGROUND: COPD is associated with an abnormal lung immune response that leads to tissue damage and remodeling of the lung, but also to systemic effects that compromise immune responses. Cigarette smoking also impacts on innate and adaptative immune responses, exerting dual, pro- and anti-inflammatory effects. Previously, we showed that COPD patients presented accelerated telomere shortening and decreased telomerase activity, while, paradoxically, cigarette-smokers exhibited preserved telomerase activity and slower rate of telomere shortening.RESULTS: Here, we evaluated the naive, CM, EM and TEMRA subsets of TCD4 and TCD8 cells according to the expression of CCR7/CD45RA. We compared age-matched COPD patients, cigarette-smokers without clinical-laboratory evidence of pulmonary compromise, and healthy individuals. They were additionally compared with a group of young adults. For each subset we analysed the expression of markers associated with late differentiation, senescence and exhaustion (CD27/CD28/CD57/KLRG1/PD1). We show that COPD patients presented a drastically reduced naive cells pool, and, paradoxically, increased fractions of naive cells expressing late differentiation, senescence or exhaustion markers, likely impacting on their immunocompetence. Pronounced phenotypic alterations were also evidenced in their three memory T-cell subsets compared with the other aged and young groups, suggesting an also dysfunctional memory pool. Surprisingly, our smokers showed a profile closer to the Healthy aged than COPD patients. They exhibited the usual age-associated shift of naive to EM TCD4 and TCD8 cells, but not to CM or TEMRA T-cells. Nonetheless, their naive T-cells phenotypes were in general similar to those of the Youngs and Healthy aged, suggesting a rather phenotypically preserved subset, while the memory T-cells exhibited increased proportions of cells with the late-differentiation or senescence/exhaustion markers as in the Healthy aged.
    CONCLUSION: Our study extends previous findings by showing that COPD patients have cells expressing a full range of late differentiated, senescent or exhausted phenotypes encompassing all TCD4 and TCD8 subsets, consistent with a premature immunosenescence phenotype. Surprisingly, the smokers group's results suggest that moderate to heavy chronic cigarette smoking did not accelerate the pace of immunosenescence as compared with the Healthy aged.
    Keywords:  Aging; COPD; Cellular senescence; Cigarette smoke; Immunophenotyping; Immunosenescence
  2. Front Immunol. 2022 ;13 806906
      Memory CD8+ T cells accumulate with aging, while the naïve T cell compartment decreases, leading to an increased susceptibility to infections and a decreased vaccine efficiency. To get deeper insights into the underlying mechanisms, this study aims to determine the age-dependent expression profile of total versus memory CD8+ T cells from young and old donors. Total CD8+ and CD8+CD45RA- memory T cells isolated from young (<30 years) and old (>60 years) donors were stimulated with anti-CD3 and anti-CD28 antibodies for 48h before analyzing the cytokine secretion and activation markers by flow cytometry and changes in the expression profiles using RNA sequencing. Gene ontology (GO) term enrichment analyses were performed for up-regulated and uniquely expressed transcripts identified in the T cell populations of both age groups. Total and memory CD8+ T cells from old donors expressed significantly higher CD25 levels and have an increased cytokine secretion. While approximately 1,500 up-regulated transcripts were identified in all groups, CD8+CD45RA- memory T cells of old donors had approximately 500 more uniquely expressed transcripts. Four GO terms related to the JAK-STAT pathway were identified for up-regulated transcripts in the total CD8+ T cells of old donors, whereas CD8+CD45RA- memory T cells GO terms related to adjacent pathways, like JNK and MAPK/ERK, were found. Additionally, the unique transcripts of CD8+CD45RA- memory T cells of old donors were related to the JNK, MAPK and IL-12 pathways. For both T cell populations of the old donors, cytokine and JAK-STAT pathway transcripts were up-regulated. Thus, an age-dependent effect was observed on the transcriptomes of total and memory CD8+ T cells. The CD8+ CD45RA- memory T cells from old donors maintained the increased cytokine secretion of the total CD8+ T cell population and the increased JAK-STAT pathway transcripts, which have an impact on inflammation and senescence.
    Keywords:  CD8+; GO terms; JAK/STAT pathway; RNA sequencing; T cells; aging; memory T cells
  3. Nat Cell Biol. 2022 Feb;24(2): 148-154
      Metabolic characteristics of adult stem cells are distinct from their differentiated progeny, and cellular metabolism is emerging as a potential driver of cell fate conversions1-4. How these metabolic features are established remains unclear. Here we identified inherited metabolism imposed by functionally distinct mitochondrial age-classes as a fate determinant in asymmetric division of epithelial stem-like cells. While chronologically old mitochondria support oxidative respiration, the electron transport chain of new organelles is proteomically immature and they respire less. After cell division, selectively segregated mitochondrial age-classes elicit a metabolic bias in progeny cells, with oxidative energy metabolism promoting differentiation in cells that inherit old mitochondria. Cells that inherit newly synthesized mitochondria with low levels of Rieske iron-sulfur polypeptide 1 have a higher pentose phosphate pathway activity, which promotes de novo purine biosynthesis and redox balance, and is required to maintain stemness during early fate determination after division. Our results demonstrate that fate decisions are susceptible to intrinsic metabolic bias imposed by selectively inherited mitochondria.
  4. Cell Rep. 2022 02 15. pii: S2211-1247(22)00110-3. [Epub ahead of print]38(7): 110389
      Liver sinusoidal endothelial cells (LSECs) are liver-resident antigen (cross)-presenting cells that generate memory CD8 T cells, but metabolic properties of LSECs and LSEC-primed CD8 T cells remain understudied. Here, we report that high-level mitochondrial respiration and constitutive low-level glycolysis support LSEC scavenger and sentinel functions. LSECs fail to increase glycolysis and co-stimulation after TLR4 activation, indicating absence of metabolic and functional maturation compared with immunogenic dendritic cells. LSEC-primed CD8 T cells show a transient burst of oxidative phosphorylation and glycolysis. Mechanistically, co-stimulatory IL-6 signaling ensures high FOXO1 expression in LSEC-primed CD8 T cells, curtails metabolic activity associated with T cell activation, and is indispensable for T cell functionality after re-activation. Thus, distinct immunometabolic features characterize non-immunogenic LSECs compared with immunogenic dendritic cells and LSEC-primed CD8 T cells with memory features compared with effector CD8 T cells. This reveals local features of metabolism and function of T cells in the liver.
    Keywords:  glycolysis; immune cell metabolism; liver immune tolerance; memory T cells; mitochondrial respiration; non-professional antigen-presenting cells
  5. Mol Nutr Food Res. 2022 Feb 19. e2100944
      SCOPE: T cell activation requires a metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis to rapidly provide substrates for biosynthesis. An individual's zinc status plays an important role in balancing the activation of T cells and is required for a proper function of immune cells. Furthermore, zinc plays an important role during effector T cell polarization to T helper cell subsets or regulatory T cells, with effector T cells relying on glycolysis and regulatory T cells on oxidative phosphorylation. Therefore, we aimed to analyze if zinc also impacts on T cell activation on the level of intracellular metabolism.METHODS AND RESULTS: We used mixed lymphocyte culture and anti-CD3/CD28 stimulation as in vitro models for T cell activation to investigate the effect of zinc supplementation and deprivation on metabolic switching. We observed promoted glucose uptake, insulin receptor expression and signaling in both zinc conditions, whereas key metabolic enzymes were stimulated mainly by zinc deprivation. Alterations in cytokine production suggest an immune-activating effect of zinc deprivation and a balancing effect of zinc supplementation.
    CONCLUSION: Our results suggest a supportive effect of both zinc supplementation and deprivation on the metabolic switch during T cell activation, adding another level of immune regulation by zinc. This article is protected by copyright. All rights reserved.
    Keywords:  T cell; zinc ; glycolytic switch; immunology; metabolism
  6. Sci Signal. 2022 Feb 15. 15(721): eabi9983
      To perform their antiviral and antitumor functions, T cells must integrate signals both from the T cell receptor (TCR), which instruct the cell to remain quiescent or become activated, and from cytokines that guide cellular proliferation and differentiation. In mature CD8+ T cells, Themis has been implicated in integrating TCR and cytokine signals. We investigated whether Themis plays a direct role in cytokine signaling in mature T cells. Themis was required for IL-2- and IL-15-driven CD8+ T cell proliferation both in mice and in vitro. Mechanistically, we found that Themis promoted the activation of the transcription factor Stat and mechanistic target of rapamycin signaling downstream of cytokine receptors. Metabolomics and stable isotope tracing analyses revealed that Themis deficiency reduced glycolysis and serine and nucleotide biosynthesis, demonstrating a receptor-proximal requirement for Themis in triggering the metabolic changes that enable T cell proliferation. The cellular, metabolic, and biochemical defects caused by Themis deficiency were corrected in mice lacking both Themis and the phosphatase Shp1, suggesting that Themis mediates IL-2 and IL-15 receptor-proximal signaling by restraining the activity of Shp1. Together, these results not only shed light on the mechanisms of cytokine signaling but also provide new clues on manipulating T cells for clinical applications.
  7. Cell Rep. 2022 02 15. pii: S2211-1247(22)00084-5. [Epub ahead of print]38(7): 110363
      Thymic atrophy reduces naive T cell production and contributes to increased susceptibility to viral infection with age. Expression of tissue-restricted antigen (TRA) genes also declines with age and has been thought to increase autoimmune disease susceptibility. We find that diminished expression of a model TRA gene in aged thymic stromal cells correlates with impaired clonal deletion of cognate T cells recognizing an autoantigen involved in atherosclerosis. Clonal deletion in the polyclonal thymocyte population is also perturbed. Distinct age-associated defects in the generation of antigen-specific T cells include a conspicuous decline in generation of T cells recognizing an immunodominant influenza epitope. Increased catalase activity delays thymic atrophy, and here, we show that it mitigates declining production of influenza-specific T cells and their frequency in lung after infection, but does not reverse declines in TRA expression or efficient negative selection. These results reveal important considerations for strategies to restore thymic function.
    Keywords:  autoimmunity; central tolerance; immunosenescence; thymus
  8. Cancer Cell. 2022 Feb 10. pii: S1535-6108(22)00037-X. [Epub ahead of print]
      Tumor-infiltrated T cells with stem-cell-like properties are important for determining the immunotherapy response. In this issue of Cancer Cell, Asrir and colleagues show that their entry requires specialized tumor-associated endothelial cells that resemble immature and inflamed lymph node vessels and that immunotherapy enhances the recruitment capacity of these endothelial cells.
  9. Cells. 2022 Jan 21. pii: 359. [Epub ahead of print]11(3):
      Acute inflammation is a physiological response to injury or infection, with a cascade of steps that ultimately lead to the recruitment of immune cells to clear invading pathogens and heal wounds. However, chronic inflammation arising from the continued presence of the initial trigger, or the dysfunction of signalling and/or effector pathways, is harmful to health. While successful ageing in older adults, including centenarians, is associated with low levels of inflammation, elevated inflammation increases the risk of poor health and death. Hence inflammation has been described as one of seven pillars of ageing. Age-associated sterile, chronic, and low-grade inflammation is commonly termed inflammageing-it is not simply a consequence of increasing chronological age, but is also a marker of biological ageing, multimorbidity, and mortality risk. While inflammageing was initially thought to be caused by "continuous antigenic load and stress", reports from the last two decades describe a much more complex phenomenon also involving cellular senescence and the ageing of the immune system. In this review, we explore some of the main sources and consequences of inflammageing in the context of immunosenescence and highlight potential interventions. In particular, we assess the contribution of cellular senescence to age-associated inflammation, identify patterns of pro- and anti-inflammatory markers characteristic of inflammageing, describe alterations in the ageing immune system that lead to elevated inflammation, and finally assess the ways that diet, exercise, and pharmacological interventions can reduce inflammageing and thus, improve later life health.
    Keywords:  SASP; ageing; cytokines; immunosenescence; immunosurveillance; inflammageing; inflammation; senescence
  10. Glycoconj J. 2022 Feb 14.
      The molecular diversity of glycosphingolipids (GSLs) that arouse during the course of evolution clearly plays an essential role in maintenance of biological homeostasis. Why is such a wide variety of GSLs necessary, and what gave rise to the expression mechanisms that are selective and specific to individual cells, tissues, or organs? What is the biological significance of these mechanisms? The same questions apply to GSLs involved in T cell development and activation. Primary CD4+ T cells and CD8+ T cells preferentially express differing ganglioside series: a-series and o-series, respectively. Conversely, a-series and o-series ganglioside deficiency results respectively in CD4+ and CD8+ T cell dysfunction. Dynamic changes in ganglioside expression occur during T cell development in thymus. Ganglioside GM3 synthase deficiency, which results in lack of a-series gangliosides, ameliorated CD4+ T cell-mediated airway hypersensitivity in a mouse model of allergic asthma. In this review, we summarize findings from these and many studies to illustrate the key roles of gangliosides in T cell differentiation and function.
    Keywords:  CD4 + T cell; CD8 + T cell; D-PDMP; Gangliosides; Immunological synapse; Lipid raft; T cell receptor (TCR)
  11. Semin Cancer Biol. 2022 Feb 10. pii: S1044-579X(22)00031-1. [Epub ahead of print]
      Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) or programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) have led to significant improvements in the overall survival of patients with certain cancers and are expected to benefit patients by achieving complete, long-lasting remissions and cure. However, some patients who receive ICIs either fail treatment or eventually develop immunotherapy resistance. The existence of such patients necessitates a deeper understanding of cancer progression, specifically nutrient regulation in the tumor microenvironment (TME), which includes both metabolic cross-talk between metabolites and tumor cells, and intracellular metabolism in immune and cancer cells. Here we review the features and behaviors of the TME and discuss the recently identified major immune checkpoints. We comprehensively and systematically summarize the metabolic modulation of tumor immunity and immune checkpoints in the TME, including glycolysis, amino acid metabolism, lipid metabolism, and other metabolic pathways, and further discuss the potential metabolism-based therapeutic strategies tested in preclinical and clinical settings. These findings will help to determine the existence of a link or crosstalk between tumor metabolism and immunotherapy, which will provide an important insight into cancer treatment and cancer research.
    Keywords:  Amine acid metabolism; Fatty acid synthesis; Glycolysis; Immune checkpoint; Immunotherapy; Lipid metabolism; Tumor metabolism; Tumor microenvironment