bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2020–12–20
twelve papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Lactate Limits T Cell Proliferation via the NAD(H) Redox State.
  2. FXR mediates T cell-intrinsic responses to reduced feeding during infection.
  3. Targeting cellular senescence as a new approach to chronic obstructive pulmonary disease therapy.
  4. Is nuclear sirtuin SIRT6 a master regulator of immune function?
  5. Redox regulation of immunometabolism.
  6. Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses.
  7. Anti-tumour immunity induces aberrant peptide presentation in melanoma.
  8. De novo synthesis and salvage pathway coordinately regulate polyamine homeostasis and determine T cell proliferation and function.
  9. PD-1 blockade restores helper activity of tumor-infiltrating exhausted PD-1hiCD39+ CD4 T cells.
  10. Metabolic Regulation of Epigenetic Modifications and Cell Differentiation in Cancer.
  11. CD57+ Memory T Cells Proliferate In Vivo.
  12. 4-1BB co-stimulation further enhances anti-PD-1-mediated reinvigoration of exhausted CD39+ CD8 T cells from primary and metastatic sites of epithelial ovarian cancers.
  1. Cell Rep. 2020 Dec 15. pii: S2211-1247(20)31489-3. [Epub ahead of print]33(11): 108500
    Lactate Limits T Cell Proliferation via the NAD(H) Redox State.
    William J Quinn, Jing Jiao, Tara TeSlaa, Jason Stadanlick, Zhonglin Wang, Liqing Wang, Tatiana Akimova, Alessia Angelin, Patrick M Schäfer, Michelle D Cully, Caroline Perry, Piotr K Kopinski, Lili Guo, Ian A Blair, Louis R Ghanem, Michael S Leibowitz, Wayne W Hancock, Edmund K Moon, Matthew H Levine, Evgeniy B Eruslanov, Douglas C Wallace, Joseph A Baur, Ulf H Beier.
      Immune cell function is influenced by metabolic conditions. Low-glucose, high-lactate environments, such as the placenta, gastrointestinal tract, and the tumor microenvironment, are immunosuppressive, especially for glycolysis-dependent effector T cells. We report that nicotinamide adenine dinucleotide (NAD+), which is reduced to NADH by lactate dehydrogenase in lactate-rich conditions, is a key point of metabolic control in T cells. Reduced NADH is not available for NAD+-dependent enzymatic reactions involving glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and 3-phosphoglycerate dehydrogenase (PGDH). We show that increased lactate leads to a block at GAPDH and PGDH, leading to the depletion of post-GAPDH glycolytic intermediates, as well as the 3-phosphoglycerate derivative serine that is known to be important for T cell proliferation. Supplementing serine rescues the ability of T cells to proliferate in the presence of lactate-induced reductive stress. Directly targeting the redox state may be a useful approach for developing novel immunotherapies in cancer and therapeutic immunosuppression.
    Keywords:  3-phosphoglycerate; T cell metabolism; glycolysis; immunometabolism; lactate metabolism; nicotinamide adenine dinucleotide; redox metabolism; serine
    DOI:  https://doi.org/10.1016/j.celrep.2020.108500
  2. Proc Natl Acad Sci U S A. 2020 Dec 14. pii: 202020619. [Epub ahead of print]
    FXR mediates T cell-intrinsic responses to reduced feeding during infection.
    Clarissa Campbell, Francois Marchildon, Anthony J Michaels, Naofumi Takemoto, Joris van der Veeken, Michail Schizas, Yuri Pritykin, Christina S Leslie, Andrew M Intlekofer, Paul Cohen, Alexander Y Rudensky.
      Reduced nutrient intake is a widely conserved manifestation of sickness behavior with poorly characterized effects on adaptive immune responses. During infectious challenges, naive T cells encountering their cognate antigen become activated and differentiate into highly proliferative effector T cells. Despite their evident metabolic shift upon activation, it remains unclear how effector T cells respond to changes in nutrient availability in vivo. Here, we show that spontaneous or imposed feeding reduction during infection decreases the numbers of splenic lymphocytes. Effector T cells showed cell-intrinsic responses dependent on the nuclear receptor Farnesoid X Receptor (FXR). Deletion of FXR in T cells prevented starvation-induced loss of lymphocytes and increased effector T cell fitness in nutrient-limiting conditions, but imparted greater weight loss to the host. FXR deficiency increased the contribution of glutamine and fatty acids toward respiration and enhanced cell survival under low-glucose conditions. Provision of glucose during anorexia of infection rescued effector T cells, suggesting that this sugar is a limiting nutrient for activated lymphocytes and that alternative fuel usage may affect cell survival in starved animals. Altogether, we identified a mechanism by which the host scales immune responses according to food intake, featuring FXR as a T cell-intrinsic sensor.
    Keywords:  FXR; T cells; anorexia; infection
    DOI:  https://doi.org/10.1073/pnas.2020619117
  3. Curr Opin Pharmacol. 2020 Dec 13. pii: S1471-4892(20)30131-4. [Epub ahead of print]56 68-73
    Targeting cellular senescence as a new approach to chronic obstructive pulmonary disease therapy.
    Peter J Barnes.
      Increasing evidence suggests that there is acceleration of normal lung ageing in chronic obstructive pulmonary disease (COPD), with the accumulation of senescent cells in the lung, which release an array of inflammatory proteins, which drive further senescence and disease progression. This suggests that drugs that target cellular senescence (senotherapies) may treat the underlying disease process in COPD and reduce disease progression and mortality. Several existing or future drugs may inhibit the development of cellular senescence, which is driven by chronic oxidative stress (senostatics), whereas other drugs selectively remove senescent cells (senolytics). Clinical studies of senotherapies have commenced in several age-related diseases, and these approaches appear to be safe and feasible, although no clinical studies in COPD patients have yet been reported.
    Keywords:  Ageing; Cellular senescence; Mechanistic target of rapamycin; Micro-RNA; Mitochondria; Senolytic; Sirtuin
    DOI:  https://doi.org/10.1016/j.coph.2020.11.004
  4. Am J Physiol Endocrinol Metab. 2020 Dec 14.
    Is nuclear sirtuin SIRT6 a master regulator of immune function?
    Vinodkumar B Pillai, Mahesh P Gupta.
      The ability to ward off pathogens with minimal damage to the host determines the immune system's robustness. Multiple factors, including pathogen processing, identification, secretion of mediator and effector molecules, and immune cell proliferation and differentiation into various subsets, constitute the success of mounting an effective immune response. Cellular metabolism controls all of these intricate processes. Cells utilize diverse fuel sources and switch back and forth between different metabolic pathways depending on their energy needs. The three most critical metabolic pathways on which immune cells depend to meet their energy needs are oxidative metabolism, glycolysis, and glutaminolysis. Dynamic switching between these metabolic pathways is needed for optimal function of the immune cells. Moreover, switching between these metabolic pathways needs to be tightly regulated to achieve the best results. Immune cells depend on the Warburg effect for their growth, proliferation, secretory, and effector functions. Here, we hypothesize that the sirtuin, SIRT6, could be a negative regulator of the Warburg effect. We also postulate that SIRT6 could act as a master regulator of immune cell metabolism and function by regulating critical signaling pathways.
    Keywords:  Cell-Signaling; Immune cells; Metabolism; SIRT6; Warburg effect
    DOI:  https://doi.org/10.1152/ajpendo.00483.2020
  5. Nat Rev Immunol. 2020 Dec 18.
    Redox regulation of immunometabolism.
    Jonathan Muri, Manfred Kopf.
      Metabolic pathways and redox reactions are at the core of life. In the past decade(s), numerous discoveries have shed light on how metabolic pathways determine the cellular fate and function of lymphoid and myeloid cells, giving rise to an area of research referred to as immunometabolism. Upon activation, however, immune cells not only engage specific metabolic pathways but also rearrange their oxidation-reduction (redox) system, which in turn supports metabolic reprogramming. In fact, studies addressing the redox metabolism of immune cells are an emerging field in immunology. Here, we summarize recent insights revealing the role of reactive oxygen species (ROS) and the differential requirement of the main cellular antioxidant pathways, including the components of the thioredoxin (TRX) and glutathione (GSH) pathways, as well as their transcriptional regulator NF-E2-related factor 2 (NRF2), for proliferation, survival and function of T cells, B cells and macrophages.
    DOI:  https://doi.org/10.1038/s41577-020-00478-8
  6. Elife. 2020 Dec 15. pii: e57950. [Epub ahead of print]9
    Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses.
    Ghada Alsaleh, Isabel Panse, Leo Swadling, Hanlin Zhang, Felix Clemens Richter, Alain Meyer, Janet Lord, Eleanor Barnes, Paul Klenerman, Christopher Green, Anna Katharina Simon.
      Vaccines are powerful tools to develop immune memory to infectious diseases and prevent excess mortality. In older adults, however vaccines are generally less efficacious and the molecular mechanisms that underpin this remain largely unknown. Autophagy, a process known to prevent aging, is critical for the maintenance of immune memory in mice. Here, we show that autophagy is specifically induced in vaccine-induced antigen-specific CD8+ T cells in healthy human volunteers. In addition, reduced IFNγ secretion by RSV-induced T cells in older vaccinees correlates with low autophagy levels. We demonstrate that levels of the endogenous autophagy-inducing metabolite spermidine fall in human T cells with age. Spermidine supplementation in T cells from old donors recovers their autophagy level and function, similar to young donors' cells, in which spermidine biosynthesis has been inhibited. Finally, our data show that endogenous spermidine maintains autophagy via the translation factor eIF5A and transcription factor TFEB. In summary, we have provided evidence for the importance of autophagy in vaccine immunogenicity in older humans and uncovered two novel drug targets that may increase vaccination efficiency in the aging context.
    Keywords:  TFEB; autophagy; human; human T cells; immunology; inflammation; spermidine; vaccine
    DOI:  https://doi.org/10.7554/eLife.57950
  7. Nature. 2020 Dec 16.
    Anti-tumour immunity induces aberrant peptide presentation in melanoma.
    Osnat Bartok, Abhijeet Pataskar, Remco Nagel, Maarja Laos, Eden Goldfarb, Deborah Hayoun, Ronen Levy, Pierre-Rene Körner, Inger Z M Kreuger, Julien Champagne, Esther A Zaal, Onno B Bleijerveld, Xinyao Huang, Juliana Kenski, Jennifer Wargo, Alexander Brandis, Yishai Levin, Orel Mizrahi, Michal Alon, Sacha Lebon, Weiwen Yang, Morten M Nielsen, Noam Stern-Ginossar, Maarten Altelaar, Celia R Berkers, Tamar Geiger, Daniel S Peeper, Johanna Olweus, Yardena Samuels, Reuven Agami.
      Extensive tumour inflammation, which is reflected by high levels of infiltrating T cells and interferon-γ (IFNγ) signalling, improves the response of patients with melanoma to checkpoint immunotherapy1,2. Many tumours, however, escape by activating cellular pathways that lead to immunosuppression. One such mechanism is the production of tryptophan metabolites along the kynurenine pathway by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which is induced by IFNγ3-5. However, clinical trials using inhibition of IDO1 in combination with blockade of the PD1 pathway in patients with melanoma did not improve the efficacy of treatment compared to PD1 pathway blockade alone6,7, pointing to an incomplete understanding of the role of IDO1 and the consequent degradation of tryptophan in mRNA translation and cancer progression. Here we used ribosome profiling in melanoma cells to investigate the effects of prolonged IFNγ treatment on mRNA translation. Notably, we observed accumulations of ribosomes downstream of tryptophan codons, along with their expected stalling at the tryptophan codon. This suggested that ribosomes bypass tryptophan codons in the absence of tryptophan. A detailed examination of these tryptophan-associated accumulations of ribosomes-which we term 'W-bumps'-showed that they were characterized by ribosomal frameshifting events. Consistently, reporter assays combined with proteomic and immunopeptidomic analyses demonstrated the induction of ribosomal frameshifting, and the generation and presentation of aberrant trans-frame peptides at the cell surface after treatment with IFNγ. Priming of naive T cells from healthy donors with aberrant peptides induced peptide-specific T cells. Together, our results suggest that IDO1-mediated depletion of tryptophan, which is induced by IFNγ, has a role in the immune recognition of melanoma cells by contributing to diversification of the peptidome landscape.
    DOI:  https://doi.org/10.1038/s41586-020-03054-1
  8. Sci Adv. 2020 Dec;pii: eabc4275. [Epub ahead of print]6(51):
    De novo synthesis and salvage pathway coordinately regulate polyamine homeostasis and determine T cell proliferation and function.
    Ruohan Wu, Xuyong Chen, Siwen Kang, Tingting Wang, Jn Rashida Gnanaprakasam, Yufeng Yao, Lingling Liu, Gaofeng Fan, Mark R Burns, Ruoning Wang.
      Robust and effective T cell-mediated immune responses require proper allocation of metabolic resources through metabolic pathways to sustain the energetically costly immune response. As an essential class of polycationic metabolites ubiquitously present in all living organisms, the polyamine pool is tightly regulated by biosynthesis and salvage pathway. We demonstrated that arginine is a major carbon donor and glutamine is a minor carbon donor for polyamine biosynthesis in T cells. Accordingly, the dependence of T cells can be partially relieved by replenishing the polyamine pool. In response to the blockage of biosynthesis, T cells can rapidly restore the polyamine pool through a compensatory increase in extracellular polyamine uptake, indicating a layer of metabolic plasticity. Simultaneously blocking synthesis and uptake depletes the intracellular polyamine pool, inhibits T cell proliferation, and suppresses T cell inflammation, indicating the potential therapeutic value of targeting the polyamine pool for managing inflammatory and autoimmune diseases.
    DOI:  https://doi.org/10.1126/sciadv.abc4275
  9. JCI Insight. 2020 Dec 17. pii: 142513. [Epub ahead of print]
    PD-1 blockade restores helper activity of tumor-infiltrating exhausted PD-1hiCD39+ CD4 T cells.
    Camille-Charlotte Balança, Anna Salvioni, Clara-Maria Scarlata, Marie Michelas, Carlos Martinez-Gomez, Carlos Gomez-Roca, Victor Sarradin, Marie Tosolini, Carine Valle, Frédéric Pont, Gwénaël Ferron, Laurence Gladieff, Sébastien Vergez, Agnès Dupret-Bories, Eliane Mery, Philippe Rochaix, Jean-Jacques Fournié, Jean-Pierre Delord, Christel Devaud, Alejandra Martinez, Maha Ayyoub.
      Tumor antigen-specific CD4 T cells accumulate at tumor sites evoking their involvement in antitumor effector functions in situ. Contrarily to CD8 cytotoxic T-lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic and functional approaches, we characterized CD4 T-cell exhaustion in head and neck, cervical and ovarian cancer patients. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression suggesting divergence with CD8 T-cell exhaustion. ScRNA-Seq and further phenotypic analyses uncovered, however, similarities with the CD8 T-cell exhaustion program. In particular, PD-1hiCD39+ CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen-specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently to higher tumor-specific CD8 T-cell proliferation. Our data identify CD4 TIL exhaustion as a player of responsiveness to immune checkpoint blockade.
    Keywords:  Cancer immunotherapy; Immunology; T cells
    DOI:  https://doi.org/10.1172/jci.insight.142513
  10. Cancers (Basel). 2020 Dec 16. pii: E3788. [Epub ahead of print]12(12):
    Metabolic Regulation of Epigenetic Modifications and Cell Differentiation in Cancer.
    Pasquale Saggese, Assunta Sellitto, Cesar A Martinez, Giorgio Giurato, Giovanni Nassa, Francesca Rizzo, Roberta Tarallo, Claudio Scafoglio.
      Metabolic reprogramming is a hallmark of cancer, with consistent rewiring of glucose, glutamine, and mitochondrial metabolism. While these metabolic alterations are adequate to meet the metabolic needs of cell growth and proliferation, the changes in critical metabolites have also consequences for the regulation of the cell differentiation state. Cancer evolution is characterized by progression towards a poorly differentiated, stem-like phenotype, and epigenetic modulation of the chromatin structure is an important prerequisite for the maintenance of an undifferentiated state by repression of lineage-specific genes. Epigenetic modifiers depend on intermediates of cellular metabolism both as substrates and as co-factors. Therefore, the metabolic reprogramming that occurs in cancer likely plays an important role in the process of the de-differentiation characteristic of the neoplastic process. Here, we review the epigenetic consequences of metabolic reprogramming in cancer, with particular focus on the role of mitochondrial intermediates and hypoxia in the regulation of cellular de-differentiation. We also discuss therapeutic implications.
    Keywords:  cancer epigenetics; cancer metabolism; cell differentiation in cancer; mitochondrial metabolism
    DOI:  https://doi.org/10.3390/cancers12123788
  11. Cell Rep. 2020 Dec 15. pii: S2211-1247(20)31490-X. [Epub ahead of print]33(11): 108501
    CD57+ Memory T Cells Proliferate In Vivo.
    Raya Ahmed, Kelly L Miners, Julio Lahoz-Beneytez, Rhiannon E Jones, Laureline Roger, Christina Baboonian, Yan Zhang, Eddie C Y Wang, Marc K Hellerstein, Joseph M McCune, Duncan M Baird, David A Price, Derek C Macallan, Becca Asquith, Kristin Ladell.
      A central paradigm in the field of lymphocyte biology asserts that replicatively senescent memory T cells express the carbohydrate epitope CD57. These cells nonetheless accumulate with age and expand numerically in response to persistent antigenic stimulation. Here, we use in vivo deuterium labeling and ex vivo analyses of telomere length, telomerase activity, and intracellular expression of the cell-cycle marker Ki67 to distinguish between two non-exclusive scenarios: (1) CD57+ memory T cells do not proliferate and instead arise via phenotypic transition from the CD57- memory T cell pool; and/or (2) CD57+ memory T cells self-renew via intracompartmental proliferation. Our results provide compelling evidence in favor of the latter scenario and further suggest in conjunction with mathematical modeling that self-renewal is by far the most abundant source of newly generated CD57+ memory T cells. Immunological memory therefore appears to be intrinsically sustainable among highly differentiated subsets of T cells that express CD57.
    Keywords:  Enter keywords here
    DOI:  https://doi.org/10.1016/j.celrep.2020.108501
  12. J Immunother Cancer. 2020 Dec;pii: e001650. [Epub ahead of print]8(2):
    4-1BB co-stimulation further enhances anti-PD-1-mediated reinvigoration of exhausted CD39+ CD8 T cells from primary and metastatic sites of epithelial ovarian cancers.
    Galam Leem, Junsik Park, Minwoo Jeon, Eui-Soon Kim, Sang Wun Kim, Yong Jae Lee, Seong Jin Choi, Baekgyu Choi, Seongyeol Park, Young Seok Ju, Inkyung Jung, Sunghoon Kim, Eui-Cheol Shin, Jung Yun Lee, Su-Hyung Park.
       BACKGROUND: Responses to immunotherapy vary between different cancer types and sites. Here, we aimed to investigate features of exhaustion and activation in tumor-infiltrating CD8 T cells at both the primary and metastatic sites in epithelial ovarian cancer.
    METHODS: Tumor tissues and peripheral blood were obtained from 65 patients with ovarian cancer. From these samples, we isolated tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells. These cells were used for immunophenotype using multicolor flow cytometry, gene expression profile using RNA sequencing and ex vivo functional restoration assays.
    RESULTS: We found that CD39+ CD8 TILs were enriched with tumor-specific CD8 TILs, and that the activation status of these cells was determined by the differential programmed cell death protein 1 (PD-1) expression level. CD39+ CD8 TILs with high PD-1 expression (PD-1high) exhibited features of highly tumor-reactive and terminally exhausted phenotypes. Notably, PD-1high CD39+ CD8 TILs showed similar characteristics in terms of T-cell exhaustion and activation between the primary and metastatic sites. Among co-stimulatory receptors, 4-1BB was exclusively overexpressed in CD39+ CD8 TILs, especially on PD-1high cells, and 4-1BB-expressing cells displayed immunophenotypes indicating higher degrees of T-cell activation and proliferation, and less exhaustion, compared with cells not expressing 4-1BB. Importantly, 4-1BB agonistic antibodies further enhanced the anti-PD-1-mediated reinvigoration of exhausted CD8 TILs from both primary and metastatic sites.
    CONCLUSION: Severely exhausted PD-1high CD39+ CD8 TILs displayed a distinctly heterogeneous exhaustion and activation status determined by differential 4-1BB expression levels, providing rationale and evidence for immunotherapies targeting co-stimulatory receptor 4-1BB in ovarian cancers.
    Keywords:  CD8-positive T-lymphocytes; adaptive immunity; immunity; lymphocytes; tumor-infiltrating
    DOI:  https://doi.org/10.1136/jitc-2020-001650
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