bims-imseme 2020-07-26 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2020‒07‒26
twenty-four papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

Dysfunctional T Cell Mitochondria Lead to Premature Aging.
CRISPR/Cas systems to overcome challenges in developing the next generation of T cells for cancer therapy.
Tumor-induced Metabolism and T Cells Located in Tumor Environment.
Reconstitution of T Cell Subsets Following Allogeneic Hematopoietic Cell Transplantation.
CD38: T Cell Immuno-Metabolic Modulator.
Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying mechanism for mouse progerias.
P2X7 receptor activity limits accumulation of T cells within tumors.
Engineering CD4+ T Cells to Enhance Cancer Immunity.
Metabolic plasticity of HIV-specific CD8+ T cells is associated with enhanced antiviral potential and natural control of HIV-1 infection.
Senolytic Drugs: From Discovery to Translation.
T Lymphocytes in Patients With Nijmegen Breakage Syndrome Demonstrate Features of Exhaustion and Senescence in Flow Cytometric Evaluation of Maturation Pathway.
Resveratrol ameliorates thymus senescence changes in D-galactose induced mice.
T cell-specific deletion of Pgam1 reveals a critical role for glycolysis in T cell responses.
Ketogenesis activates metabolically protective γδ T cells in visceral adipose tissue.
Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction.
Engineering the Bridge between Innate and Adaptive Immunity for Cancer Immunotherapy: Focus on γδ T and NK Cells.
Aging, Cellular Senescence, and Progressive Multiple Sclerosis.
Hematopoietic Stem Cell Metabolism during Development and Aging.
CD4+CD25-FoxP3+ T cells: a distinct subset or a heterogeneous population?
Exploring the Influence of Cell Metabolism on Cell Fate through Protein Post-translational Modifications.
The metabolic tug of war between HIV and T cells.
Peroxisome Proliferator-Activated Receptors and Caloric Restriction-Common Pathways Affecting Metabolism, Health, and Longevity.
Metabolic signaling in T cells.
NAD+: a metabolic knob fine-tuning inflammation during senescence.

Trends Mol Med. 2020 Jul 22. pii: S1471-4914(20)30160-X. [Epub ahead of print]

Dysfunctional T Cell Mitochondria Lead to Premature Aging.

Guy Lenaers, Dominique Bonneau, Yves Delneste, Nicolas Papon.

  Desdín-Micó et al. have shown that Tfam specific knockout in mouse T cells disrupts mitochondrial genome integrity and induces a burst of inflammatory cytokines and tumor necrosis factor (TNF)-α production, resulting in increased senescence, neuromuscular and vascular dysfunction, and molecular features that recapitulate premature aging. Interestingly, treatment with nicotinamide riboside (NR) alleviates this phenotype by reducing senescence and systemic inflammation.

Keywords:  T cells; cytokine; mitochondria; premature aging; senescence

DOI:  https://doi.org/10.1016/j.molmed.2020.07.001
Adv Drug Deliv Rev. 2020 Jul 21. pii: S0169-409X(20)30099-5. [Epub ahead of print]

CRISPR/Cas systems to overcome challenges in developing the next generation of T cells for cancer therapy.

Dennis Huang, Matthew Miller, Bhaargavi Ashok, Samagra Jain, Nicholas A Peppas.

  Genetically engineered immune cells with chimeric antigen receptors (CAR) or modified T cell receptors (TCR) have demonstrated their potential as a potent class of new cancer therapeutic strategy. Despite the clinical success of autologous CD19 CAR T cells in hematological malignancies, allogeneic T cells exhibit many advantages over their autologous counterparts and have recently gathered widespread attention due to the emergence of multiplex genome editing techniques, particularly CRISPR/Cas systems. Furthermore, genetically engineered T cells face a host of major challenges in solid tumors that are not as significant for blood cancers such as T cell targeted delivery, target specificity, proliferation, persistence, and the immunosuppressive tumor microenvironment. We take this opportunity to analyze recent strategies to develop allogeneic T cells, specifically in consideration of CRISPR/Cas and its delivery systems for multiplex gene editing. Additionally, we discuss the current methods used to delivery CRISPR/Cas systems for immunotherapeutic applications, and the challenges to continued development of novel delivery systems. We also provide a comprehensive analysis of the major challenges that genetically engineered T cells face in solid tumors along with the most recent strategies to overcome these barriers, with an emphasis on CRISPR-based approaches. We illustrate the synergistic prospects for how the combination of synthetic biology and immune-oncology could pave the way for designing the next generation of precision cancer therapy.

Keywords:  Adoptive cell therapy; Allogeneic T cells; CRISPR/Cas delivery systems; Cancer immunotherapy; Chimeric antigen receptor; Solid tumor

DOI:  https://doi.org/10.1016/j.addr.2020.07.015
Curr Cancer Drug Targets. 2020 Jul 19.

Tumor-induced Metabolism and T Cells Located in Tumor Environment.

Sara Iranparast, Sanaz Tayebi, Fatemeh Ahmadpour, Bahman Yousefi.

  Several subtypes of T cells are located in a tumor environment, each of which supplies their energy using different metabolic mechanisms. Since the cancer cells require high levels of glucose, the conditions of food poverty in the tumor environment can cause inactivation of immune cells, especially the T-effector cells, due to the need for glucose in the early stages of these cells activity. Different signaling pathways such as PI3K-AKt-mTOR, MAPK, HIF-1α, etc active or inactive by the amount and type of energy source or oxygen levels that determine the fate of T cells in a cancerous environment. This review describes the metabolites in the tumor environment and their effects on the function of T cells. It also explains the signaling pathway of T cells in the tumor and normal conditions, due to the level of access to available metabolites and subtypes of T cells in the tumor environment.

Keywords:  T lymphocytes; cancer; cytokines.; immune evasion; immunotherapy; metabolism

DOI:  https://doi.org/10.2174/1568009620666200720010647
Cancers (Basel). 2020 Jul 20. pii: E1974. [Epub ahead of print]12(7):

Reconstitution of T Cell Subsets Following Allogeneic Hematopoietic Cell Transplantation.

Linde Dekker, Coco de Koning, Caroline Lindemans, Stefan Nierkens.

  Allogeneic (allo) hematopoietic cell transplantation (HCT) is the only curative treatment option for patients suffering from chemotherapy-refractory or relapsed hematological malignancies. The occurrence of morbidity and mortality after allo-HCT is still high. This is partly correlated with the immunological recovery of the T cell subsets, of which the dynamics and relations to complications are still poorly understood. Detailed information on T cell subset recovery is crucial to provide tools for better prediction and modulation of adverse events. Here, we review the current knowledge regarding CD4+ and CD8+ T cells, γδ T cells, iNKT cells, Treg cells, MAIT cells and naive and memory T cell reconstitution, as well as their relations to outcome, considering different cell sources and immunosuppressive therapies. We conclude that the T cell subsets reconstitute in different ways and are associated with distinct adverse and beneficial events; however, adequate reconstitution of all the subsets is associated with better overall survival. Although the exact mechanisms involved in the reconstitution of each T cell subset and their associations with allo-HCT outcome need to be further elucidated, the data and suggestions presented here point towards the development of individualized approaches to improve their reconstitution. This includes the modulation of immunotherapeutic interventions based on more detailed immune monitoring, aiming to improve overall survival changes.

Keywords:  T cell subsets; allogeneic hematopoietic cell transplantation; biomarkers; conditioning; hematological malignancies; immune reconstitution; immunosuppressive therapies; serotherapy

DOI:  https://doi.org/10.3390/cancers12071974
Cells. 2020 Jul 17. pii: E1716. [Epub ahead of print]9(7):

CD38: T Cell Immuno-Metabolic Modulator.

Anwesha Kar, Shikhar Mehrotra, Shilpak Chatterjee.

  Activation and subsequent differentiation of T cells following antigenic stimulation are triggered by highly coordinated signaling events that lead to instilling cells with a discrete metabolic and transcriptional feature. Compelling studies indicate that intracellular nicotinamide adenine dinucleotide (NAD+) levels have profound influence on diverse signaling and metabolic pathways of T cells, and hence dictate their functional fate. CD38, a major mammalian NAD+ glycohydrolase (NADase), expresses on T cells following activation and appears to be an essential modulator of intracellular NAD+ levels. The enzymatic activity of CD38 in the process of generating the second messenger cADPR utilizes intracellular NAD+, and thus limits its availability to different NAD+ consuming enzymes (PARP, ART, and sirtuins) inside the cells. The present review discusses how the CD38-NAD+ axis affects T cell activation and differentiation through interfering with their signaling and metabolic processes. We also describe the pivotal role of the CD38-NAD+ axis in influencing the chromatin remodeling and rewiring T cell response. Overall, this review emphasizes the crucial contribution of the CD38-NAD+ axis in altering T cell response in various pathophysiological conditions.

Keywords:  CD38; NAD+, T cell differentiation; chromatin remodeling; metabolism

DOI:  https://doi.org/10.3390/cells9071716
Nat Metab. 2019 Oct;1(10): 958-965

Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying mechanism for mouse progerias.

Riikka H Hämäläinen, Juan C Landoni, Kati J Ahlqvist, Steffi Goffart, Sanna Ryytty, M Obaidur Rahman, Virginia Brilhante, Katherine Icay, Sampsa Hautaniemi, Liya Wang, Marikki Laiho, Anu Suomalainen.

Mitochondrial DNA (mtDNA) mutagenesis and nuclear DNA repair defects are considered cellular mechanisms of ageing. mtDNA mutator mice with increased mtDNA mutagenesis show signs of premature ageing. However, why patients with mitochondrial diseases, or mice with other forms of mitochondrial dysfunction, do not age prematurely remains unknown. Here, we show that cells from mutator mice display challenged nuclear genome maintenance similar to that observed in progeric cells with defects in nuclear DNA repair. Cells from mutator mice show slow nuclear DNA replication fork progression, cell cycle stalling and chronic DNA replication stress, leading to double-strand DNA breaks in proliferating progenitor or stem cells. The underlying mechanism involves increased mtDNA replication frequency, sequestering of nucleotides to mitochondria, depletion of total cellular nucleotide pools, decreased deoxynucleoside 5'-triphosphate (dNTP) availability for nuclear genome replication and compromised nuclear genome maintenance. Our data indicate that defects in mtDNA replication can challenge nuclear genome stability. We suggest that defects in nuclear genome maintenance, particularly in the stem cell compartment, represent a unified mechanism for mouse progerias. Therefore, through their destabilizing effects on the nuclear genome, mtDNA mutations are indirect contributors to organismal ageing, suggesting that the direct role of mtDNA mutations in driving ageing-like symptoms might need to be revisited.

DOI: https://doi.org/10.1038/s42255-019-0120-1
Cancer Res. 2020 Jul 22. pii: canres.3807.2019. [Epub ahead of print]

P2X7 receptor activity limits accumulation of T cells within tumors.

Andrea Romagnani, Elsa Rottoli, Emilia Maria Cristina Mazza, Tanja Rezzonico-Jost, Benedetta De Ponte Conti, Michele Proietti, Michela Perotti, Elisa Civanelli, Lisa Perruzza, Alberico L Catapano, Andrea Baragetti, Elena Tenedini, Enrico Tagliafico, Simonetta Falzoni, Francesco Di Virgilio, Giuseppe Danilo Norata, Silvio Bicciato, Fabio Grassi.

Extracellular adenosine triphosphate (eATP) is a signaling molecule which variably affects all cells of the immune system either directly or after hydrolysis to adenosine. Although eATP is virtually absent in the interstitium of normal tissues, it can be present in the hundreds of micromolar range in tumors, a concentration compatible with activation of the ATP-gated ionotropic P2X7 receptor. Here we show that P2X7 activity in tumor-infiltrating T cells (TILs) induces cellular senescence and limits tumor suppression. P2X7 stimulation affected cell cycling of effector T cells and resulted in generation of mitochondrial reactive oxygen species (ROS) and p38 MAPK-dependent upregulation of cyclin-dependent kinase inhibitor 1A (Cdkn1a, encoding for p21Waf1/Cip1). Lack of P2X7 promoted a transcriptional signature that correlated with enhanced cytotoxic T cell response in human solid tumors. In mice, transfer of tumor specific T cells with deletion of P2rx7 significantly reduced tumor growth and extended survival. Collectively, these findings uncover a purinergic checkpoint that can be targeted to improve the efficacy of cancer immunotherapy strategies.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-3807
Cells. 2020 Jul 18. pii: E1721. [Epub ahead of print]9(7):

Engineering CD4+ T Cells to Enhance Cancer Immunity.

Francesca Sillito, Angelika Holler, Hans J Stauss.

  This review presents key advances in combining T cell receptor (TCR) gene transfer to redirect T-cell specificity with gene engineering in order to enhance cancer-protective immune function. We discuss how emerging insights might be applied to CD4+ T cells. Although much attention has been paid to the role of CD8+ cytotoxic T cells in tumour protection, we provide convincing evidence that CD4+ helper T cells play a critical role in cancer immune responses in animal models and also in patients. We demonstrate that genetic engineering technologies provide exciting opportunities to extend the specificity range of CD4+ T cells from MHC class-II-presented epitopes to include peptides presented by MHC class I molecules. Functional enhancement of tumour immunity can improve the sensitivity of T cells to cancer antigens, promote survival in a hostile tumour microenvironment, boost cancer-protective effector mechanisms and enable the formation of T-cell memory. Engineered cancer-specific CD4+ T cells may contribute to protective immunity by a direct pathway involving cancer cell killing, and by an indirect pathway that boosts the function, persistence and memory formation of CD8+ T cells.

Keywords:  T cell receptor (TCR); T helper cell (Th); interferon-gamma (IFN-γ); major histocompatibility complex (MHC); mechanistic target of Rapamycin 1 (mTORC1); programmed death receptor 1 (PD-1)

DOI:  https://doi.org/10.3390/cells9071721
Nat Metab. 2019 Jul;1(7): 704-716

Metabolic plasticity of HIV-specific CD8+ T cells is associated with enhanced antiviral potential and natural control of HIV-1 infection.

Mathieu Angin, Stevenn Volant, Caroline Passaes, Camille Lecuroux, Valérie Monceaux, Marie-Agnès Dillies, José Carlos Valle-Casuso, Gianfranco Pancino, Bruno Vaslin, Roger Le Grand, Laurence Weiss, Cecile Goujard, Laurence Meyer, Faroudy Boufassa, Michaela Müller-Trutwin, Olivier Lambotte, Asier Sáez-Cirión.

Spontaneous control of human immunodeficiency virus (HIV) is generally associated with an enhanced capacity of CD8+ T cells to eliminate infected CD4+ T cells, but the molecular characteristics of these highly functional CD8+ T cells are largely unknown. In the present study, using single-cell analysis, it was shown that HIV-specific, central memory CD8+ T cells from spontaneous HIV controllers (HICs) and antiretrovirally treated non-controllers have opposing transcriptomic profiles. Genes linked to effector functions and survival are upregulated in cells from HICs. In contrast, genes associated with activation, exhaustion and glycolysis are upregulated in cells from non-controllers. It was shown that HIV-specific CD8+ T cells from non-controllers are largely glucose dependent, whereas those from HICs have more diverse metabolic resources that enhance both their survival potential and their capacity to develop anti-HIV effector functions. The functional efficiency of the HIV-specific CD8+ T cell response in HICs is thus engraved in their memory population and related to their metabolic programme. Metabolic reprogramming in vitro through interleukin-15 treatment abrogated the glucose dependency and enhanced the antiviral potency of HIV-specific CD8+ T cells from non-controllers.

DOI: https://doi.org/10.1038/s42255-019-0081-4
J Intern Med. 2020 Jul 19.

Senolytic Drugs: From Discovery to Translation.

James L Kirkland, Tamar Tchkonia.

  Senolytics are a class of drugs that selectively clear senescent cells (SC). The first senolytic drugs Dasatinib, Quercetin, Fisetin, and Navitoclax were discovered using a hypothesis-driven approach. SC accumulate with aging and at causal sites of multiple chronic disorders, including diseases accounting for the bulk of morbidity, mortality, and health expenditures. The most deleterious SC are resistant to apoptosis and have up-regulation of anti-apoptotic pathways which defend SC against their own inflammatory senescence-associated secretory phenotype (SASP), allowing them to survive, despite killing neighboring cells. Senolytics transiently disable these SCAPs, causing apoptosis of those SC with a tissue-destructive SASP. Because SC take weeks to re-accumulate, senolytics can be administered intermittently - a "hit-and-run" approach. In pre-clinical models, senolytics delay, prevent, or alleviate frailty, cancers, and cardiovascular, neuropsychiatric, liver, kidney, musculoskeletal, lung, eye, hematological, metabolic, and skin disorders as well as complications of organ transplantation, radiation, and cancer treatment. As anticipated for agents targeting the fundamental aging mechanisms that are "root cause" contributors to multiple disorders, potential uses of senolytics are protean, potentially alleviating over 40 conditions in preclinical studies, opening a new route for treating age-related dysfunction and diseases. Early pilot trials of senolytics suggest they decrease senescent cells, reduce inflammation, and alleviate frailty in humans. Clinical trials for diabetes, idiopathic pulmonary fibrosis, Alzheimer's disease, COVID-19, osteoarthritis, osteoporosis, eye diseases, and bone marrow transplant and childhood cancer survivors are underway or beginning. Until such studies are done, it is too early for senolytics to be used outside of clinical trials.

Keywords:  Dasatinib; Fisetin; Quercetin; Senescent Cell Anti-Apoptotic Pathways (SCAPs); Senolytics; Unitary Theory of Fundamental Aging Processes

DOI:  https://doi.org/10.1111/joim.13141
Front Immunol. 2020 ;11 1319

T Lymphocytes in Patients With Nijmegen Breakage Syndrome Demonstrate Features of Exhaustion and Senescence in Flow Cytometric Evaluation of Maturation Pathway.

Barbara Piatosa, Beata Wolska-Kuśnierz, Katarzyna Tkaczyk, Edyta Heropolitanska-Pliszka, Urszula Grycuk, Anna Wakulinska, Hanna Gregorek.

  Patients with Nijmegen Breakage Syndrome (NBS) suffer from recurrent infections due to humoral and cellular immune deficiency. Despite low number of T lymphocytes and their maturation defect, the clinical manifestations of cell-mediated deficiency are not as severe as in case of patients with other types of combined immune deficiencies and similar T cell lymphopenia. In this study, multicolor flow cytometry was used for evaluation of peripheral T lymphocyte maturation according to the currently known differentiation pathway, in 46 patients with genetically confirmed NBS and 46 sex and age-matched controls. Evaluation of differential expression of CD27, CD31, CD45RA, CD95, and CD197 revealed existence of cell subsets so far not described in NBS patients. Although recent thymic emigrants and naïve T lymphocyte cell populations were significantly lower, the generation of antigen-primed T cells was similar or even greater in NBS patients than in healthy controls. Moreover, the senescent and exhausted T cell populations defined by expression of CD57, KLRG1, and PD1 were more numerous than in healthy people. Although this hypothesis needs further investigations, such properties might be related to an increased susceptibility to malignancy and milder clinical course than expected in view of T cell lymphopenia in patients with NBS.

Keywords:  Nijmegen Breakage Syndrome; T lymphocyte maturation; flow cytometry; immune exhaustion; immune senescence; primary immune deficiency

DOI:  https://doi.org/10.3389/fimmu.2020.01319
Microbiol Immunol. 2020 Jul 21.

Resveratrol ameliorates thymus senescence changes in D-galactose induced mice.

Ting-Ting Wei, Meng-Jie Li, Li Guo, Yan-Dong Xie, Wen-Hui Chen, Yun Sun, Guo-Hong Liu, Yi Ding, Yu-Rong Chai.

  Thymic microenvironment plays an important role in the development of T cells. The decrease of thymic epithelial cells is the main cause of age-related thymic atrophy or degeneration. Resveratrol (RSV), a phytoalexin produced from plants, has been shown to inhibit the adverse effects of dietary obesity on the structure and function of thymus. D-galactose (D-gal) can induce accelerated aging in mice. In the present study, the young mice (2-month-old) were injected with D-gal (120 mg/kg/d) for 8 consecutive weeks to construct accelerated aging model. Compared with normal control mice, the thymus epithelium of the D-gal treated mice had structural changes, the number of senescent cells increased, and the number of CD4+ T cells decreased and CD8+ T cells increased. After RSV administration by gavage for 6 weeks, it was found that RSV improved surface phenotypes of D-gal treated mice, and recovered thymus function by maintaining the ratio of CD4+ and CD8+ cells. It also indicated that RSV enhanced the cells proliferation and inhibited cellular senescence. Increased autoimmune regulator (Aire) expression was presented in the RSV treated mice. The Lymphotoxin-beta receptor (LTβR) expression also increased. These findings suggest that RSV intake could restore the alterations caused by D-gal treatment in the thymus via stimulation of Aire expression. This article is protected by copyright. All rights reserved.

Keywords:  Aging; Aire; D-galactose; Resveratrol; Thymus

DOI:  https://doi.org/10.1111/1348-0421.12833
Commun Biol. 2020 Jul 24. 3(1): 394

T cell-specific deletion of Pgam1 reveals a critical role for glycolysis in T cell responses.

Koji Toriyama, Makoto Kuwahara, Hiroshi Kondoh, Takumi Mikawa, Nobuaki Takemori, Amane Konishi, Toshihiro Yorozuya, Takeshi Yamada, Tomoyoshi Soga, Atsushi Shiraishi, Masakatsu Yamashita.

Although the important roles of glycolysis in T cells have been demonstrated, the regulatory mechanism of glycolysis in activated T cells has not been fully elucidated. Furthermore, the influences of glycolytic failure on the T cell-dependent immune response in vivo remain unclear. We therefore assessed the role of glycolysis in the T cell-dependent immune response using T cell-specific Pgam1-deficient mice. Both CD8 and CD4 T cell-dependent immune responses were attenuated by Pgam1 deficiency. The helper T cell-dependent inflammation was ameliorated in Pgam1-deficient mice. Glycolysis augments the activation of mTOR complex 1 (mTORC1) and the T-cell receptor (TCR) signals. Glutamine acts as a metabolic hub in activated T cells, since the TCR-dependent increase in intracellular glutamine is required to augment glycolysis, increase mTORC1 activity and augment TCR signals. These findings suggest that mTORC1, glycolysis and glutamine affect each other and cooperate to induce T cell proliferation and differentiation.

DOI: https://doi.org/10.1038/s42003-020-01122-w
Nat Metab. 2020 Jan;2(1): 50-61

Ketogenesis activates metabolically protective γδ T cells in visceral adipose tissue.

Emily L Goldberg, Irina Shchukina, Jennifer L Asher, Sviatoslav Sidorov, Maxim N Artyomov, Vishwa Deep Dixit.

Ketone bodies are essential alternative fuels that allow humans to survive periods of glucose scarcity induced by starvation and prolonged exercise. A widely used ketogenic diet (KD), which is extremely high in fat with very low carbohydrates, drives the host into using β-hydroxybutyrate for the production of ATP and lowers NLRP3-mediated inflammation. However, the extremely high fat composition of KD raises the question of how ketogenesis affects adipose tissue to control inflammation and energy homeostasis. Here, by using single-cell RNA sequencing of adipose-tissue-resident immune cells, we show that KD expands metabolically protective γδ T cells that restrain inflammation. Notably, long-term ad libitum KD feeding in mice causes obesity, impairs metabolic health and depletes the adipose-resident γδ T cells. In addition, mice lacking γδ T cells have impaired glucose homeostasis. Our results suggest that γδ T cells are mediators of protective immunometabolic responses that link fatty acid-driven fuel use to reduced adipose tissue inflammation.

DOI: https://doi.org/10.1038/s42255-019-0160-6
Nat Metab. 2020 Jul;2(7): 635-647

Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction.

Tingting Wang, J N Rashida Gnanaprakasam, Xuyong Chen, Siwen Kang, Xuequn Xu, Hua Sun, Lingling Liu, Hayley Rodgers, Ethan Miller, Teresa A Cassel, Qiushi Sun, Sara Vicente-Muñoz, Marc O Warmoes, Penghui Lin, Zayda Lizbeth Piedra-Quintero, Mireia Guerau-de-Arellano, Kevin A Cassady, Song Guo Zheng, Jun Yang, Andrew N Lane, Xiaotong Song, Teresa W-M Fan, Ruoning Wang.

T cells undergo metabolic rewiring to meet their bioenergetic, biosynthetic and redox demands following antigen stimulation. To fulfil these needs, effector T cells must adapt to fluctuations in environmental nutrient levels at sites of infection and inflammation. Here, we show that effector T cells can utilize inosine, as an alternative substrate, to support cell growth and function in the absence of glucose in vitro. T cells metabolize inosine into hypoxanthine and phosphorylated ribose by purine nucleoside phosphorylase. We demonstrate that the ribose subunit of inosine can enter into central metabolic pathways to provide ATP and biosynthetic precursors, and that cancer cells display diverse capacities to utilize inosine as a carbon source. Moreover, the supplementation with inosine enhances the anti-tumour efficacy of immune checkpoint blockade and adoptive T-cell transfer in solid tumours that are defective in metabolizing inosine, reflecting the capability of inosine to relieve tumour-imposed metabolic restrictions on T cells.

DOI: https://doi.org/10.1038/s42255-020-0219-4
Cells. 2020 Jul 22. pii: E1757. [Epub ahead of print]9(8):

Engineering the Bridge between Innate and Adaptive Immunity for Cancer Immunotherapy: Focus on γδ T and NK Cells.

Fabio Morandi, Mahboubeh Yazdanifar, Claudia Cocco, Alice Bertaina, Irma Airoldi.

  Most studies on genetic engineering technologies for cancer immunotherapy based on allogeneic donors have focused on adaptive immunity. However, the main limitation of such approaches is that they can lead to severe graft-versus-host disease (GvHD). An alternative approach would bolster innate immunity by relying on the natural tropism of some subsets of the innate immune system, such as γδ T and natural killer (NK) cells, for the tumor microenvironment and their ability to kill in a major histocompatibility complex (MHC)-independent manner. γδ T and NK cells have the unique ability to bridge innate and adaptive immunity while responding to a broad range of tumors. Considering these properties, γδ T and NK cells represent ideal sources for developing allogeneic cell therapies. Recently, significant efforts have been made to exploit the intrinsic anti-tumor capacity of these cells for treating hematologic and solid malignancies using genetic engineering approaches such as chimeric antigen receptor (CAR) and T cell receptor (TCR). Here, we review over 30 studies on these two approaches that use γδ T and NK cells in adoptive cell therapy (ACT) for treating cancer. Based on those studies, we propose several promising strategies to optimize the clinical translation of these approaches.

Keywords:  CAR-T cell; GvHD; NK cells; TCR transfer; adoptive cell therapy; engineered T cell; gamma delta T cells; immunotherapy; γδT cells

DOI:  https://doi.org/10.3390/cells9081757
Front Cell Neurosci. 2020 ;14 178

Aging, Cellular Senescence, and Progressive Multiple Sclerosis.

Dimitrios Papadopoulos, Roberta Magliozzi, Dimos D Mitsikostas, Vassilis G Gorgoulis, Richard S Nicholas.

  Aging is one of the most important risk factors for the development of several neurodegenerative diseases including progressive multiple sclerosis (MS). Cellular senescence (CS) is a key biological process underlying aging. Several stressors associated with aging and MS pathology, such as oxidative stress, mitochondrial dysfunction, cytokines and replicative exhaustion are known triggers of cellular senescence. Senescent cells exhibit stereotypical metabolic and functional changes, which include cell-cycle arrest and acquiring a pro-inflammatory phenotype secreting cytokines, growth factors, metalloproteinases and reactive oxygen species. They accumulate with aging and can convert neighboring cells to senescence in a paracrine manner. In MS, accelerated cellular senescence may drive disease progression by promoting chronic non-remitting inflammation, loss or altered immune, glial and neuronal function, failure of remyelination, impaired blood-brain barrier integrity and ultimately neurodegeneration. Here we discuss the evidence linking cellular senescence to the pathogenesis of MS and the putative role of senolytic and senomorphic agents as neuroprotective therapies in tackling disease progression.

Keywords:  cellular senescence; inflammation; multiple sclerosis; neurodegeneration; neuroprotection; remyelination; senolytics

DOI:  https://doi.org/10.3389/fncel.2020.00178
Dev Cell. 2020 Jul 20. pii: S1534-5807(20)30537-2. [Epub ahead of print]54(2): 239-255

Hematopoietic Stem Cell Metabolism during Development and Aging.

Ayako Nakamura-Ishizu, Keisuke Ito, Toshio Suda.

Cellular metabolism in hematopoietic stem cells (HSCs) is an area of intense research interest, but the metabolic requirements of HSCs and their adaptations to their niches during development have remained largely unaddressed. Distinctive from other tissue stem cells, HSCs transition through multiple hematopoietic sites during development. This transition requires drastic metabolic shifts, insinuating the capacity of HSCs to meet the physiological demand of hematopoiesis. In this review, we highlight how mitochondrial metabolism determines HSC fate, and especially focus on the links between mitochondria, endoplasmic reticulum (ER), and lysosomes in HSC metabolism.

DOI: https://doi.org/10.1016/j.devcel.2020.06.029
Int Rev Immunol. 2020 Jul 24. 1-10

CD4+CD25-FoxP3+ T cells: a distinct subset or a heterogeneous population?

Mahshid Zohouri, Fereshteh Mehdipour, Mahboobeh Razmkhah, Zahra Faghih, Abbas Ghaderi.

  In addition to generating effective immunity against infectious agents, the immune system helps to fight against different noninfectious human diseases while maintaining the balance between self and non-self discrimination. The breakdown of tolerance in autoimmune diseases or sustainable tolerance in an abnormal microenvironment such as chronic inflammation may initiate the process of malignancy. Immune system regulation is controlled by a complex, dynamic network of cells and mediators. Understanding the cellular and molecular basis of immune regulation provides better insight into the mechanisms governing the immune pathology of diseases. Among several cellular subsets and mediators with regulatory roles, a subpopulation of CD4+ T cells was recently reported to be positive for FoxP3 and negative for CD25, with a suggested range of functional activities in both cancer and autoimmune diseases. This CD4 subset was first reported in 2006 and thought to have a role in the pathogenesis of cancer. However, the spectrum of roles played by this T cell subset is broad, and no consensus has been reached regarding its immunological functions. In this review, we focused on the possible origin of CD4+CD25‒FoxP3+ T cells and their function in cancer and autoimmune diseases.

Keywords:  CD25; FoxP3; autoimmunity; cancer

DOI:  https://doi.org/10.1080/08830185.2020.1797005
Dev Cell. 2020 Jul 20. pii: S1534-5807(20)30543-8. [Epub ahead of print]54(2): 282-292

Exploring the Influence of Cell Metabolism on Cell Fate through Protein Post-translational Modifications.

Oscar A Tarazona, Olivier Pourquié.

The connection between cell fate transitions and metabolic shifts is gaining momentum in the study of cell differentiation in embryonic development, adult stem cells, and cancer pathogenesis. Here, we explore how metabolic transitions influence post-translational modifications (PTMs), which play central roles in the activation of transcriptional programs. PTMs can control the function of transcription factors acting as master regulators of cell fate as well as activation or repression of cell identity genes by regulating chromatin state via histone tail modifications. It now becomes clear that cell metabolism is an integral part of the complex landscape of regulatory mechanisms underlying cell differentiation.

DOI: https://doi.org/10.1016/j.devcel.2020.06.035
Nat Metab. 2019 Jul;1(7): 653-655

The metabolic tug of war between HIV and T cells.

Ramon I Klein Geltink.

DOI: https://doi.org/10.1038/s42255-019-0091-2
Cells. 2020 Jul 16. pii: E1708. [Epub ahead of print]9(7):

Peroxisome Proliferator-Activated Receptors and Caloric Restriction-Common Pathways Affecting Metabolism, Health, and Longevity.

Kalina Duszka, András Gregor, Hervé Guillou, Jürgen König, Walter Wahli.

  Caloric restriction (CR) is a traditional but scientifically verified approach to promoting health and increasing lifespan. CR exerts its effects through multiple molecular pathways that trigger major metabolic adaptations. It influences key nutrient and energy-sensing pathways including mammalian target of rapamycin, Sirtuin 1, AMP-activated protein kinase, and insulin signaling, ultimately resulting in reductions in basic metabolic rate, inflammation, and oxidative stress, as well as increased autophagy and mitochondrial efficiency. CR shares multiple overlapping pathways with peroxisome proliferator-activated receptors (PPARs), particularly in energy metabolism and inflammation. Consequently, several lines of evidence suggest that PPARs might be indispensable for beneficial outcomes related to CR. In this review, we present the available evidence for the interconnection between CR and PPARs, highlighting their shared pathways and analyzing their interaction. We also discuss the possible contributions of PPARs to the effects of CR on whole organism outcomes.

Keywords:  PPARs; caloric restriction; nuclear receptors; nutrition

DOI:  https://doi.org/10.3390/cells9071708
Cell Res. 2020 Jul 24.

Metabolic signaling in T cells.

Justin A Shyer, Richard A Flavell, Will Bailis.

The maintenance of organismal homeostasis requires partitioning and transport of biochemical molecules between organ systems, their composite cells, and subcellular organelles. Although transcriptional programming undeniably defines the functional state of cells and tissues, underlying biochemical networks are intricately intertwined with transcriptional, translational, and post-translational regulation. Studies of the metabolic regulation of immunity have elegantly illustrated this phenomenon. The cells of the immune system interface with a diverse set of environmental conditions. Circulating immune cells perfuse peripheral organs in the blood and lymph, patrolling for pathogen invasion. Resident immune cells remain in tissues and play more newly appreciated roles in tissue homeostasis and immunity. Each of these cell populations interacts with unique and dynamic tissue environments, which vary greatly in biochemical composition. Furthermore, the effector response of immune cells to a diverse set of activating cues requires unique cellular adaptations to supply the requisite biochemical landscape. In this review, we examine the role of spatial partitioning of metabolic processes in immune function. We focus on studies of lymphocyte metabolism, with reference to the greater immunometabolism literature when appropriate to illustrate this concept.

DOI: https://doi.org/10.1038/s41422-020-0379-5
Nat Metab. 2019 Mar;1(3): 310-311

NAD+: a metabolic knob fine-tuning inflammation during senescence.

Pia Pernille Søgaard, Jesús Gil.

DOI: https://doi.org/10.1038/s42255-019-0047-6