bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021–10–31
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Fueling T-cell Antitumor Immunity: Amino Acid Metabolism Revisited.
  2. Accelerated Maturation, Exhaustion, and Senescence of T cells in 22q11.2 Deletion Syndrome.
  3. Understanding T cell aging to improve anti-viral immunity.
  4. Multilayer omics analysis reveals a non-classical retinoic acid signaling axis that regulates hematopoietic stem cell identity.
  5. Strategies for late phase preclinical and early clinical trials of senolytics.
  6. Hypoxia Reduction Sensitizes Refractory Cancers to Immunotherapy.
  7. Enhanced Gut-Homing Dynamics and Pronounced Exhaustion of Mucosal and Blood CD4+ T Cells in HIV-Infected Immunological Non-Responders.
  8. Cell Cycle Entry Control in Naïve and Memory CD8+ T Cells.
  9. 6-Phosphogluconate dehydrogenase (6PGD), a key checkpoint in reprogramming of regulatory T cells metabolism and function.
  10. Histone H4 lysine 16 acetylation controls central carbon metabolism and diet-induced obesity in mice.
  11. Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy.
  12. SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells.
  13. Daily caloric restriction limits tumor growth more effectively than caloric cycling regardless of dietary composition.
  1. Cancer Immunol Res. 2021 Oct 29.
    Fueling T-cell Antitumor Immunity: Amino Acid Metabolism Revisited.
    Chenfeng Han, Minmin Ge, Ping-Chih Ho, Lianjun Zhang.
      T cells are the key players in eliminating malignant tumors. Adoptive transfer of tumor antigen-specific T cells and immune checkpoint blockade has yielded durable antitumor responses in the clinic, but not all patients respond initially and some that do respond eventually have tumor progression. Thus, new approaches to enhance the utility of immunotherapy are needed. T-cell activation and differentiation status are tightly controlled at the transcriptional, epigenetic, and metabolic levels. Amino acids are involved in multiple steps of T-cell antitumor immunity, including T-cell activation, proliferation, effector function, memory formation as well as functional exhaustion. In this review, we briefly discuss how amino acid metabolism is linked to T-cell fate decisions and summarize how amino acid deprivation or accumulation of certain amino acid metabolites within the tumor microenvironment diminishes T-cell functionality. Furthermore, we discuss potential strategies for immunotherapy via modulating amino acid metabolism either in T cells intrinsically or extrinsically to achieve therapeutic efficacy.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-21-0459
  2. J Clin Immunol. 2021 Oct 29.
    Accelerated Maturation, Exhaustion, and Senescence of T cells in 22q11.2 Deletion Syndrome.
    Jitka Smetanova, Tomas Milota, Michal Rataj, Marketa Bloomfield, Anna Sediva, Adam Klocperk.
       PURPOSE: 22q11.2 deletion syndrome (22q11.2DS) is a primary immunodeficiency characterized chiefly by the hypoplasia of the thymus resulting in T cell lymphopenia, increased susceptibility to infections, and higher risk of autoimmune diseases. The irregular thymic niche of T cell development may contribute to autoimmune and atopic complications, whereas the compensatory mechanism of homeostatic T cell proliferation and continuous immune stimulation may result in T cell senescence and exhaustion, further aggravating the immune system dysregulation.
    METHODS: We used flow cytometry to investigate T cell maturation, delineation, proliferation, activation, and expression of senescence and exhaustion-associated markers (PD1, KLRG1, CD57) in 17 pediatric and adolescent patients with 22q11.2DS and age-matched healthy donors.
    RESULTS: 22q11.2DS patients aged 0-5 years had fewer naïve but more effector memory T cells with a tendency to approach normal values with increasing age. Young patients in particular had a higher percentage of proliferating T cells and increased expression of PD1, KLRG1, and CD57, as well as cells co-expressing several exhaustion-associated molecules (PD1, KLRG1, Tbet, Eomes, Helios). Additionally, high-risk 22q11.2DS patients with very low numbers of CD4 T cells had significantly higher percentage of Th1 and Th17 T cells, driven in part by higher proportion of mature T cell forms.
    CONCLUSION: The low thymic output and accelerated T cell differentiation remain the principal features of 22q11.2DS patient immunity, especially in young patients of < 5 years. Later in life, homeostatic proliferation drives expression of T cell exhaustion and senescence-associated markers, suggesting functional aberrations in addition to numeric T cell deficiency.
    Keywords:  22q11.2 deletion syndrome; CD57; DiGeorge syndrome; PD1; T cells; differentiation; immunodeficiency; maturation; thymus
    DOI:  https://doi.org/10.1007/s10875-021-01154-9
  3. Curr Opin Virol. 2021 Oct 21. pii: S1879-6257(21)00122-X. [Epub ahead of print]51 127-133
    Understanding T cell aging to improve anti-viral immunity.
    Huimin Zhang, Cornelia M Weyand, Jörg J Goronzy, Claire E Gustafson.
      T cells are a critical component of the immune system and required for protection against viral and bacterial infections. However, the capacity of these cells to provide sufficient protection declines with age, leading to an increased susceptibility to and mortality from infection in older individuals. In many cases, it also contributes to poor vaccine-induced immunity. Understanding the basic biology behind T cell aging is key to unraveling these defects and, in turn, designing more effective vaccines and therapeutics for the older population. Here, we will discuss recent studies that have provided significant insight into the features of T cell aging, how these features may contribute to poor immune responses with advancing age and newer avenues of research that may further enhance anti-viral immunity in older individuals.
    DOI:  https://doi.org/10.1016/j.coviro.2021.09.017
  4. Cell Stem Cell. 2021 Oct 20. pii: S1934-5909(21)00414-8. [Epub ahead of print]
    Multilayer omics analysis reveals a non-classical retinoic acid signaling axis that regulates hematopoietic stem cell identity.
    Katharina Schönberger, Nadine Obier, Mari Carmen Romero-Mulero, Pierre Cauchy, Julian Mess, Polina V Pavlovich, Yu Wei Zhang, Michael Mitterer, Jasmin Rettkowski, Maria-Eleni Lalioti, Karin Jäcklein, Jonathan D Curtis, Betty Féret, Pia Sommerkamp, Claudia Morganti, Keisuke Ito, Norbert B Ghyselinck, Eirini Trompouki, Joerg M Buescher, Erika L Pearce, Nina Cabezas-Wallscheid.
      Hematopoietic stem cells (HSCs) rely on complex regulatory networks to preserve stemness. Due to the scarcity of HSCs, technical challenges have limited our insights into the interplay between metabolites, transcription, and the epigenome. In this study, we generated low-input metabolomics, transcriptomics, chromatin accessibility, and chromatin immunoprecipitation data , revealing distinct metabolic hubs that are enriched in HSCs and their downstream multipotent progenitors. Mechanistically, we uncover a non-classical retinoic acid (RA) signaling axis that regulates HSC function. We show that HSCs rely on Cyp26b1, an enzyme conventionally considered to limit RA effects in the cell. In contrast to the traditional view, we demonstrate that Cyp26b1 is indispensable for production of the active metabolite 4-oxo-RA. Further, RA receptor beta (Rarb) is required for complete transmission of 4-oxo-RA-mediated signaling to maintain stem cells. Our findings emphasize that a single metabolite controls stem cell fate by instructing epigenetic and transcriptional attributes.
    Keywords:  4-oxo-RA; Cyp26b1; Rarb; at-RA; epigenetics; hematopoietic stem cells; metabolites; self-renewal; vitamin A
    DOI:  https://doi.org/10.1016/j.stem.2021.10.002
  5. Mech Ageing Dev. 2021 Oct 23. pii: S0047-6374(21)00163-9. [Epub ahead of print]200 111591
    Strategies for late phase preclinical and early clinical trials of senolytics.
    Erin O Wissler Gerdes, Avanish Misra, Jair Machado Espindola Netto, Tamar Tchkonia, James L Kirkland.
      Cellular senescence and the hallmarks of aging contribute to age-related disease and dysfunction. The Unitary Theory of Fundamental Aging Mechanisms highlights the interdependence among the hallmarks of aging and suggests that by intervening in one fundamental aging process, most or all of the other processes could be impacted. Accumulation of senescent cells is associated with frailty, cardiovascular disease, obesity, diabetes, cognitive decline, and other age- and/or chronic disease-related disorders, suggesting that senescent cells are a target for intervention. Early preclinical data using senolytics, agents that target senescent cells, show promising results in several aging and disease models. The first in-human trials using the senolytic combination of Dasatinib and Quercetin indicated reduced senescent cell burden in adipose tissue of diabetic kidney disease patients and improved physical function in patients with idiopathic pulmonary fibrosis. Clinical trials with other senolytics, including the flavonoid Fisetin and BCL-xL inhibitors, are underway. These results from preclinical and early clinical trials illustrate the potential of senolytics to alleviate age-related dysfunction and diseases. However, multiple clinical trials across different aging and disease models are desperately needed. Parallel trials across institutions through the Translational Geroscience Network are facilitating testing to determine whether senolytics can be translated into clinical application.
    Keywords:  Dasatinib; Fisetin; Quercetin; Senolytics; Translational Geroscience Network; Unitary Theory of Fundamental Aging Processes
    DOI:  https://doi.org/10.1016/j.mad.2021.111591
  6. Annu Rev Med. 2021 Oct 26.
    Hypoxia Reduction Sensitizes Refractory Cancers to Immunotherapy.
    Priyamvada Jayaprakash, Paolo Dario Angelo Vignali, Greg M Delgoffe, Michael A Curran.
      In order to fuel their relentless expansion, cancers must expand their vasculature to augment delivery of oxygen and essential nutrients. The disordered web of irregular vessels that results, however, leaves gaps in oxygen delivery that foster tumor hypoxia. At the same time, tumor cells increase their oxidative metabolism to cope with the energetic demands of proliferation, which further worsens hypoxia due to heightened oxygen consumption. In these hypoxic, nutrient-deprived environments, tumors and suppressive stroma evolve to flourish while antitumor immunity collapses due to a combination of energetic deprivation, toxic metabolites, acidification, and other suppressive signals. Reversal of cancer hypoxia thus has the potential to increase the survival and effector function of tumor-infiltrating T cells, as well as to resensitize tumors to immunotherapy. Early clinical trials combining hypoxia reduction with immune checkpoint blockade have shown promising results in treating patients with advanced, metastatic, and therapeutically refractory cancers. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-med-060619-022830
  7. Front Immunol. 2021 ;12 744155
    Enhanced Gut-Homing Dynamics and Pronounced Exhaustion of Mucosal and Blood CD4+ T Cells in HIV-Infected Immunological Non-Responders.
    Kristina Berg Lorvik, Malin Holm Meyer-Myklestad, Kushi Kushekar, Charlotte Handeland, Asle Wilhelm Medhus, Marius Lund-Iversen, Birgitte Stiksrud, Dag Kvale, Anne Margarita Dyrhol-Riise, Kjetil Taskén, Dag Henrik Reikvam.
      Immunological non-responders (INR), a subgroup of people living with HIV (PLHIV) who fail to restore CD4+ T cell numbers upon effective antiretroviral treatment, have impaired gut mucosal barrier function and an inferior clinical prognosis compared with immunological responders (IR). The contribution of gut-homing and exhaustion of mucosal T cells to the INR phenotype was previously unknown. Flow cytometry analysis of mononuclear cells from peripheral blood and ileal and colonic lamina propria showed that INR had higher fractions of gut-homing CD4+ T cells in blood compared with IR. In addition, gut-homing cells were more likely to display signs of exhaustion in INR. The increased CD4+ T cell exhaustion in INR was ubiquitous and not restricted to subpopulations defined by activation, differentiation or regulatory T cell markers. In INR, colon CD4+ T cell exhaustion correlated negatively with the fraction of CD4+ T cells in the same compartment, this was not apparent in the ileum. The fraction of exhausted mucosal CD4+ T cells correlated with I-FABP and REG3α, markers of enterocyte damage. We conclude that alterations of gut-homing and exhaustion of T cells may contribute to impaired gut immune and barrier functions associated with immunological non-response in PLHIV.
    Keywords:  CD4 T cell; HIV; PD1; TIGIT; exhaustion; gut-homing CD4+ T cell; immunological non-responder; lamina propria
    DOI:  https://doi.org/10.3389/fimmu.2021.744155
  8. Front Cell Dev Biol. 2021 ;9 727441
    Cell Cycle Entry Control in Naïve and Memory CD8+ T Cells.
    David A Lewis, Tony Ly.
      CD8+ T cells play important roles in immunity and immuno-oncology. Upon antigen recognition and co-stimulation, naïve CD8+ T cells escape from dormancy to engage in a complex programme of cellular growth, cell cycle entry and differentiation, resulting in rapid proliferation cycles that has the net effect of producing clonally expanded, antigen-specific cytotoxic T lymphocytes (CTLs). A fraction of activated T cells will re-enter dormancy by differentiating into memory T cells, which have essential roles in adaptive immunity. In this review, we discuss the current understanding of cell cycle entry control in CD8+ T cells and crosstalk between these mechanisms and pathways regulating immunological phenotypes.
    Keywords:  T cell; T cell activation; cell cycle; proliferation; quiescence
    DOI:  https://doi.org/10.3389/fcell.2021.727441
  9. Elife. 2021 Oct 28. pii: e67476. [Epub ahead of print]10
    6-Phosphogluconate dehydrogenase (6PGD), a key checkpoint in reprogramming of regulatory T cells metabolism and function.
    Saeed Daneshmandi, Teresa Cassel, Richard M Higashi, Teresa W-M Fan, Pankaj Seth.
      Cellular metabolism has key roles in T cells differentiation and function. CD4+ T helper-1 (Th1), Th2, and Th17 subsets are highly glycolytic while regulatory T cells (Tregs) use glucose during expansion but rely on fatty acid oxidation for function. Upon uptake, glucose can enter pentose phosphate pathway (PPP) or be used in glycolysis. Here, we showed that blocking 6-phosphogluconate dehydrogenase (6PGD) in the oxidative PPP resulted in substantial reduction of Tregs suppressive function and shifts toward Th1, Th2, and Th17 phenotypes which led to the development of fetal inflammatory disorder in mice model. These in turn improved anti-tumor responses and worsened the outcomes of colitis model. Metabolically, 6PGD blocked Tregs showed improved glycolysis and enhanced non-oxidative PPP to support nucleotide biosynthesis. These results uncover critical role of 6PGD in modulating Tregs plasticity and function, which qualifies it as a novel metabolic checkpoint for immunotherapy applications.
    Keywords:  6PGD; cell biology; glucose; immunoregulation; metabolism; mouse; pentose phosphate pathway; regulatory T cell
    DOI:  https://doi.org/10.7554/eLife.67476
  10. Nat Commun. 2021 Oct 27. 12(1): 6212
    Histone H4 lysine 16 acetylation controls central carbon metabolism and diet-induced obesity in mice.
    Cecilia Pessoa Rodrigues, Aindrila Chatterjee, Meike Wiese, Thomas Stehle, Witold Szymanski, Maria Shvedunova, Asifa Akhtar.
      Noncommunicable diseases (NCDs) account for over 70% of deaths world-wide. Previous work has linked NCDs such as type 2 diabetes (T2D) to disruption of chromatin regulators. However, the exact molecular origins of these chronic conditions remain elusive. Here, we identify the H4 lysine 16 acetyltransferase MOF as a critical regulator of central carbon metabolism. High-throughput metabolomics unveil a systemic amino acid and carbohydrate imbalance in Mof deficient mice, manifesting in T2D predisposition. Oral glucose tolerance testing (OGTT) reveals defects in glucose assimilation and insulin secretion in these animals. Furthermore, Mof deficient mice are resistant to diet-induced fat gain due to defects in glucose uptake in adipose tissue. MOF-mediated H4K16ac deposition controls expression of the master regulator of glucose metabolism, Pparg and the entire downstream transcriptional network. Glucose uptake and lipid storage can be reconstituted in MOF-depleted adipocytes in vitro by ectopic Glut4 expression, PPARγ agonist thiazolidinedione (TZD) treatment or SIRT1 inhibition. Hence, chronic imbalance in H4K16ac promotes a destabilisation of metabolism triggering the development of a metabolic disorder, and its maintenance provides an unprecedented regulatory epigenetic mechanism controlling diet-induced obesity.
    DOI:  https://doi.org/10.1038/s41467-021-26277-w
  11. Nat Commun. 2021 Oct 28. 12(1): 6218
    Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy.
    Eric H Bent, Luis R Millán-Barea, Iris Zhuang, Daniel R Goulet, Julia Fröse, Michael T Hemann.
      Cytotoxic chemotherapeutics primarily function through DNA damage-induced tumor cell apoptosis, although the inflammation provoked by these agents can stimulate anti-cancer immune responses. The mechanisms that control these distinct effects and limit immunogenic responses to DNA-damage mediated cell death in vivo are currently unclear. Using a mouse model of BCR-ABL+ B-cell acute lymphoblastic leukemia, we show that chemotherapy-induced anti-cancer immunity is suppressed by the tumor microenvironment through production of the cytokine IL-6. The chemotherapeutic doxorubicin is curative in IL-6-deficient mice through the induction of CD8+ T-cell-mediated anti-cancer responses, while moderately extending lifespan in wild type tumor-bearing mice. We also show that IL-6 suppresses the effectiveness of immune-checkpoint inhibition with anti-PD-L1 blockade. Our results suggest that IL-6 is a key regulator of anti-cancer immune responses induced by genotoxic stress and that its inhibition can switch cancer cell clearance from primarily apoptotic to immunogenic, promoting and maintaining durable anti-tumor immune responses.
    DOI:  https://doi.org/10.1038/s41467-021-26407-4
  12. Nature. 2021 Oct 27.
    SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells.
    Ying Wang, Frederick S Yen, Xiphias Ge Zhu, Rebecca C Timson, Ross Weber, Changrui Xing, Yuyang Liu, Benjamin Allwein, Hanzhi Luo, Hsi-Wen Yeh, Søren Heissel, Gokhan Unlu, Eric R Gamazon, Michael G Kharas, Richard Hite, Kıvanç Birsoy.
      Glutathione (GSH) is a small-molecule thiol that is abundant in all eukaryotes and has key roles in oxidative metabolism1. Mitochondria, as the major site of oxidative reactions, must maintain sufficient levels of GSH to perform protective and biosynthetic functions2. GSH is synthesized exclusively in the cytosol, yet the molecular machinery involved in mitochondrial GSH import remains unknown. Here, using organellar proteomics and metabolomics approaches, we identify SLC25A39, a mitochondrial membrane carrier of unknown function, as a regulator of GSH transport into mitochondria. Loss of SLC25A39 reduces mitochondrial GSH import and abundance without affecting cellular GSH levels. Cells lacking both SLC25A39 and its paralogue SLC25A40 exhibit defects in the activity and stability of proteins containing iron-sulfur clusters. We find that mitochondrial GSH import is necessary for cell proliferation in vitro and red blood cell development in mice. Heterologous expression of an engineered bifunctional bacterial GSH biosynthetic enzyme (GshF) in mitochondria enables mitochondrial GSH production and ameliorates the metabolic and proliferative defects caused by its depletion. Finally, GSH availability negatively regulates SLC25A39 protein abundance, coupling redox homeostasis to mitochondrial GSH import in mammalian cells. Our work identifies SLC25A39 as an essential and regulated component of the mitochondrial GSH-import machinery.
    DOI:  https://doi.org/10.1038/s41586-021-04025-w
  13. Nat Commun. 2021 Oct 27. 12(1): 6201
    Daily caloric restriction limits tumor growth more effectively than caloric cycling regardless of dietary composition.
    Laura C D Pomatto-Watson, Monica Bodogai, Oye Bosompra, Jonathan Kato, Sarah Wong, Melissa Carpenter, Eleonora Duregon, Dolly Chowdhury, Priya Krishna, Sandy Ng, Emeline Ragonnaud, Roberto Salgado, Paula Gonzalez Ericsson, Alberto Diaz-Ruiz, Michel Bernier, Nathan L Price, Arya Biragyn, Valter D Longo, Rafael de Cabo.
      Cancer incidence increases with age and is a leading cause of death. Caloric restriction (CR) confers benefits on health and survival and delays cancer. However, due to CR's stringency, dietary alternatives offering the same cancer protection have become increasingly attractive. Short cycles of a plant-based diet designed to mimic fasting (FMD) are protective against tumorigenesis without the chronic restriction of calories. Yet, it is unclear whether the fasting time, level of dietary restriction, or nutrient composition is the primary driver behind cancer protection. Using a breast cancer model in mice, we compare the potency of daily CR to that of periodic caloric cycling on FMD or an isocaloric standard laboratory chow against primary tumor growth and metastatic burden. Here, we report that daily CR provides greater protection against tumor growth and metastasis to the lung, which may be in part due to the unique immune signature observed with daily CR.
    DOI:  https://doi.org/10.1038/s41467-021-26431-4
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