bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021‒12‒26
twelve papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. Int J Mol Sci. 2021 Dec 20. pii: 13668. [Epub ahead of print]22(24):
      The capacity of T cells to identify and kill cancer cells has become a central pillar of immune-based cancer therapies. However, T cells are characterized by a dysfunctional state in most tumours. A major obstacle for proper T-cell function is the metabolic constraints posed by the tumour microenvironment (TME). In the TME, T cells compete with cancer cells for macronutrients (sugar, proteins, and lipid) and micronutrients (vitamins and minerals/ions). While the role of macronutrients in T-cell activation and function is well characterized, the contribution of micronutrients and especially ions in anti-tumour T-cell activities is still under investigation. Notably, ions are important for most of the signalling pathways regulating T-cell anti-tumour function. In this review, we discuss the role of six biologically relevant ions in T-cell function and in anti-tumour immunity, elucidating potential strategies to adopt to improve immunotherapy via modulation of ion metabolism.
    Keywords:  T cell; immunomodulation; ions; nutrient competition; tumour microenvironment
  2. Biochem Biophys Res Commun. 2021 Dec 17. pii: S0006-291X(21)01685-5. [Epub ahead of print]588 34-40
      Glucocorticoids (GCs), immunosuppressive, and anti-inflammatory agents have various effects on T cells. However, the long-term influence of GCs on the T cell-mediated immune response remain to be elucidated. We demonstrated that the administration of GC during the TCR-mediated activation phase induced long-lasting suppression of glycolysis, even after the withdrawal of GC. The acquisition of the effector functions was inhibited, while the expression of PD-1 was increased in CD8 T cells activated in the presence of GC. Furthermore, adoptive transfer experiments revealed that GC-treated CD8 T cells reduced memory T cell formation and anti-tumor activity. These findings reveal that GCs have long-lasting influence on the T cell-mediated immune response via modulation of T cell metabolism.
    Keywords:  CD8 T cells; Glucocorticoid; Glycolysis; Memory T cells; Programed cell death 1; Tumor immunity
  3. Front Immunol. 2021 ;12 722320
      The inhibition of anabolic pathways, such as aerobic glycolysis, is a metabolic cornerstone of memory T cell differentiation and function. However, the signals that hamper these anabolic pathways are not completely known. Recent evidence pinpoints the chemokine receptor CCR5 as an important player in CD4+ T cell memory responses by regulating T cell antigen receptor (TCR) nanoclustering in an antigen-independent manner. This paper reports that CCR5 specifically restrains aerobic glycolysis in memory-like CD4+ T cells, but not in effector CD4+ T cells. CCR5-deficient memory CD4+ T cells thus show an abnormally high glycolytic/oxidative metabolism ratio. No CCR5-dependent change in glucose uptake nor in the expression of the main glucose transporters was detected in any of the examined cell types, although CCR5-deficient memory cells did show increased expression of the hexokinase 2 and pyruvate kinase M2 isoforms, plus the concomitant downregulation of Bcl-6, a transcriptional repressor of these key glycolytic enzymes. Further, the TCR nanoclustering defects observed in CCR5-deficient antigen-experienced CD4+ T cells were partially reversed by incubation with 2-deoxyglucose (2-DG), suggesting a link between inhibition of the glycolytic pathway and TCR nanoscopic organization. Indeed, the treatment of CCR5-deficient lymphoblasts with 2-DG enhanced IL-2 production after antigen re-stimulation. These results identify CCR5 as an important regulator of the metabolic fitness of memory CD4+ T cells, and reveal an unexpected link between T cell metabolism and TCR organization with potential influence on the response of memory T cells upon antigen re-encounter.
    Keywords:  BCL6; CCR5; chemokine signaling; efector CD4+ T cells; glycolysis; memory CD4+ T cells; metabolic reprogramming
  4. Genes (Basel). 2021 Nov 23. pii: 1856. [Epub ahead of print]12(12):
      The immune system undergoes major changes with age that result in altered immune populations, persistent inflammation, and a reduced ability to mount effective immune responses against pathogens and cancer cells. Aging-associated changes in the immune system are connected to other age-related diseases, suggesting that immune system rejuvenation may provide a feasible route to improving overall health in the elderly. The Sir2 family of proteins, also called sirtuins, have been broadly implicated in genome homeostasis, cellular metabolism, and aging. Sirtuins are key responders to cellular and environmental stress and, in the case of the nuclear sirtuins, they do so by directing responses to chromatin that include gene expression regulation, retrotransposon repression, enhanced DNA damage repair, and faithful chromosome segregation. In the immune system, sirtuins instruct cellular differentiation from hematopoietic precursors and promote leukocyte polarization and activation. In hematopoietic stem cells, sirtuins safeguard quiescence and stemness to prevent cellular exhaustion. Regulation of cytokine production, which, in many cases, requires NF-κB regulation, is the best-characterized mechanism by which sirtuins control innate immune reactivity. In adaptive immunity, sirtuins promote T cell subset differentiation by controlling master regulators, thereby ensuring an optimal balance of helper (Th) T cell-dependent responses. Sirtuins are very important for immune regulation, but the means by which they regulate immunosenescence are not well understood. This review provides an integrative overview of the changes associated with immune system aging and its potential relationship with the roles of nuclear sirtuins in immune cells and overall organismal aging. Given the anti-aging properties of sirtuins, understanding how they contribute to immune responses is of vital importance and may help us develop novel strategies to improve immune performance in the aging organism.
    Keywords:  aging; epigenetics; immune senescence; immune system; inflammation; sirtuins
  5. Cancers (Basel). 2021 Dec 11. pii: 6227. [Epub ahead of print]13(24):
      Colorectal cancer (CRC) continues to be one of the most frequently diagnosed types of cancers in the world. CRC is considered to affect mostly elderly patients, and the number of diagnosed cases increases with age. Even though general screening improves outcomes, the overall survival and recurrence-free CRC rates in aged individuals are highly dependent on their history of comorbidities. Furthermore, aging is also known to alter the immune system, and especially the adaptive immune T cells. Many studies have emphasized the importance of T cell responses to CRC. Therefore, understanding how age-related changes affect the outcome in CRC patients is crucial. This review focuses on what is so far known about age-related T cell dysfunction in elderly patients with colorectal cancer and how aged T cells can mediate its development. Last, this study describes the advances in basic animal models that have potential to be used to elucidate the role of aged T cells in CRC.
    Keywords:  CRC; T cell aging; aging; colorectal cancer; exhaustion; senescence
  6. Immunity. 2021 Dec 14. pii: S1074-7613(21)00509-4. [Epub ahead of print]
      Elevated gene expression of the costimulatory receptor Icos is a hallmark of CD8+ tissue-resident memory (Trm) T cells. Here, we examined the contribution of ICOS in Trm cell differentiation. Upon transfer into WT mice, Icos-/- CD8+ T cells exhibited defective Trm generation but produced recirculating memory populations normally. ICOS deficiency or ICOS-L blockade compromised establishment of CD8+ Trm cells but not their maintenance. ICOS ligation during CD8+ T cell priming did not determine Trm induction; rather, effector CD8+ T cells showed reduced Trm differentiation after seeding into Icosl-/- mice. IcosYF/YF CD8+ T cells were compromised in Trm generation, indicating a critical role for PI3K signaling. Modest transcriptional changes in the few Icos-/- Trm cells suggest that ICOS-PI3K signaling primarily enhances the efficiency of CD8+ T cell tissue residency. Thus, local ICOS signaling promotes production of Trm cells, providing insight into the contribution of costimulatory signals in the generation of tissue-resident populations.
    Keywords:  ICOS; PI3K; resident memory T cells
  7. Front Physiol. 2021 ;12 746749
      Lipid droplets (LDs) are commonly found in various biological cells and are organelles related to cell metabolism. LDs, the number and size of which are heterogeneous across cell type, are primarily composed of polar lipids and proteins on the surface with neutral lipids in the core. Neutral lipids stored in LDs can be degraded by lipolysis and lipophagocytosis, which are regulated by various proteins. The process of LD formation can be summarized in four steps. In addition to energy production, LDs play an extremely pivotal role in a variety of physiological and pathological processes, such as endoplasmic reticulum stress, lipid toxicity, storage of fat-soluble vitamins, regulation of oxidative stress, and reprogramming of cell metabolism. Interestingly, LDs, the hub of integration between metabolism and the immune system, are involved in antitumor immunity, anti-infective immunity (viruses, bacteria, parasites, etc.) and some metabolic immune diseases. Herein, we summarize the role of LDs in several major immune cells as elucidated in recent years, including T cells, dendritic cells, macrophages, mast cells, and neutrophils. Additionally, we analyze the role of the interaction between LDs and immune cells in two typical metabolic immune diseases: atherosclerosis and Mycobacterium tuberculosis infection.
    Keywords:  atherosclerosis; immune cells; immunity; lipid droplets; metabolism
  8. Free Radic Biol Med. 2021 Dec 15. pii: S0891-5849(21)01108-4. [Epub ahead of print]178 391-397
      Dr. Bruce Ames was a pioneer in understanding the role of oxidative stress and DNA damage, and in the 1990s began to make connections between micronutrient deficiencies and DNA damage. Zinc is an essential micronutrient for human health and a key component for the function of numerous cellular processes. In particular, zinc plays a critical role in cellular antioxidant defense, the maintenance of DNA integrity and is also essential for the normal development and function of the immune system. This review highlights the work helping connect zinc deficiency to oxidative stress, susceptibility to DNA damage and chronic inflammation that was initiated while working with Dr. Ames. This review outlines the body of work in this area, from cells to humans. The article also reviews the unique challenges of maintaining zinc status as we age and the interplay between zinc deficiency and age-related inflammation and immune dysfunction. Several micronutrient deficiencies, including zinc deficiency, can drastically affect the risk of many chronic diseases and underscores the importance of adequate nutrition for healthy aging.
    Keywords:  Aging; DNA damage; Inflammation; Oxidative stress; Zinc
  9. Antioxidants (Basel). 2021 Dec 03. pii: 1940. [Epub ahead of print]10(12):
      Reactive oxygen species (ROS) participate in the T-cell activation processes. ROS-dependent regulatory networks are usually mediated by peroxides, which are more stable and able to freely migrate inside cells. Superoxide dismutase (SOD)-1 represents the major physiological intracellular source of peroxides. We found that antigen-dependent activation represents a triggering element for SOD-1 production and secretion by human T lymphocytes. A deranged T-cell proinflammatory response characterizes the pathogenesis of multiple sclerosis (MS). We previously observed a decreased SOD-1 intracellular content in leukocytes of MS individuals at diagnosis, with increasing amounts of such enzyme after interferon (IFN)-b 1b treatment. Here, we analyzed in depth SOD-1 intracellular content in T cells in a cohort of MS individuals undergoing immune-modulating treatment. Higher amounts of the enzyme were associated with increased availability of regulatory T cells (Treg) preferentially expressing Foxp3-exon 2 (Foxp3-E2), as described for effective Treg. In vitro administration of recombinant human SOD-1 to activated T cells, significantly increased their IL-17 production, while SOD-1 molecules lacking dismutase activity were unable to interfere with cytokine production by activated T cells in vitro. Furthermore, hydrogen peroxide addition was observed to mimic, in vitro, the SOD-1 effect on IL-17 production. These data add SOD-1 to the molecules involved in the molecular pathways contributing to re-shaping the T-cell cytokine profile and Treg differentiation.
    Keywords:  SOD-1; T lymphocytes; Treg; cytokines; multiple sclerosis
  10. Science. 2021 Dec 24. 374(6575): 1632-1640
    Christine N Spencer, Jennifer L McQuade, Vancheswaran Gopalakrishnan, John A McCulloch, Marie Vetizou, Alexandria P Cogdill, Md A Wadud Khan, Xiaotao Zhang, Michael G White, Christine B Peterson, Matthew C Wong, Golnaz Morad, Theresa Rodgers, Jonathan H Badger, Beth A Helmink, Miles C Andrews, Richard R Rodrigues, Andrey Morgun, Young S Kim, Jason Roszik, Kristi L Hoffman, Jiali Zheng, Yifan Zhou, Yusra B Medik, Laura M Kahn, Sarah Johnson, Courtney W Hudgens, Khalida Wani, Pierre-Olivier Gaudreau, Angela L Harris, Mohamed A Jamal, Erez N Baruch, Eva Perez-Guijarro, Chi-Ping Day, Glenn Merlino, Barbara Pazdrak, Brooke S Lochmann, Robert A Szczepaniak-Sloane, Reetakshi Arora, Jaime Anderson, Chrystia M Zobniw, Eliza Posada, Elizabeth Sirmans, Julie Simon, Lauren E Haydu, Elizabeth M Burton, Linghua Wang, Minghao Dang, Karen Clise-Dwyer, Sarah Schneider, Thomas Chapman, Nana-Ama A S Anang, Sheila Duncan, Joseph Toker, Jared C Malke, Isabella C Glitza, Rodabe N Amaria, Hussein A Tawbi, Adi Diab, Michael K Wong, Sapna P Patel, Scott E Woodman, Michael A Davies, Merrick I Ross, Jeffrey E Gershenwald, Jeffrey E Lee, Patrick Hwu, Vanessa Jensen, Yardena Samuels, Ravid Straussman, Nadim J Ajami, Kelly C Nelson, Luigi Nezi, Joseph F Petrosino, P Andrew Futreal, Alexander J Lazar, Jianhua Hu, Robert R Jenq, Michael T Tetzlaff, Yan Yan, Wendy S Garrett, Curtis Huttenhower, Padmanee Sharma, Stephanie S Watowich, James P Allison, Lorenzo Cohen, Giorgio Trinchieri, Carrie R Daniel, Jennifer A Wargo.
      [Figure: see text].
  11. Trends Endocrinol Metab. 2021 Dec 21. pii: S1043-2760(21)00266-6. [Epub ahead of print]
      Alpha-ketoglutarate (AKG) is an intermediate in the Krebs cycle involved in various metabolic and cellular pathways. As an antioxidant, AKG interferes in nitrogen and ammonia balance, and affects epigenetic and immune regulation. These pleiotropic functions of AKG suggest it may also extend human healthspan. Recent studies in worms and mice support this concept. A few studies published in the 1980s and 1990s in humans suggested the potential benefits of AKG in muscle growth, wound healing, and in promoting faster recovery after surgery. So far there are no recently published studies demonstrating the role of AKG in treating aging and age-related diseases; hence, further clinical studies are required to better understand the role of AKG in humans. This review will discuss the regulatory role of AKG in aging, as well as its potential therapeutic use in humans to treat age-related diseases.
    Keywords:  antioxidant; cellular respiration; citric acid cycle; healthspan; ketoglutaric acids; supplement