bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022–01–09
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Mastering an exhausting marathon: how CD8+ T cells fine-tune metabolic fitness.
  2. Targeting memory T cell metabolism to improve immunity.
  3. Protein synthesis, degradation, and energy metabolism in T cell immunity.
  4. Tumor microenvironment metabolites directing T cell differentiation and function.
  5. Aging Leukocytes and the Inflammatory Microenvironment of the Adipose Tissue.
  6. Immunometabolism in bladder cancer microenvironment.
  7. Restricting tumor lactic acid metabolism using dichloroacetate improves T cell functions.
  8. Senescent immune cells release grancalcin to promote skeletal aging.
  9. Age-associated changes in cumulus cells and follicular fluid: The local oocyte microenvironment as a determinant of gamete quality.
  10. A purine metabolic checkpoint that prevents autoimmunity and autoinflammation.
  1. Immunol Cell Biol. 2022 Jan 05.
    Mastering an exhausting marathon: how CD8+ T cells fine-tune metabolic fitness.
    Anna M Schulz, Dietmar Zehn.
      A recent study by Gabriel et al. provides novel insight into the metabolic pathways that contribute to T cell differentiation in chronic infection. The researchers discovered that metabolic plasticity and the function of exhausted T cells is regulated via the TGF-β-mTOR signaling axis.
    DOI:  https://doi.org/10.1111/imcb.12517
  2. J Clin Invest. 2022 Jan 04. pii: e148546. [Epub ahead of print]132(1):
    Targeting memory T cell metabolism to improve immunity.
    Mauro Corrado, Erika L Pearce.
      Vaccination affords protection from disease by activating pathogen-specific immune cells and facilitating the development of persistent immunologic memory toward the vaccine-specific pathogen. Current vaccine regimens are often based on the efficiency of the acute immune response, and not necessarily on the generation of memory cells, in part because the mechanisms underlying the development of efficient immune memory remain incompletely understood. This Review describes recent advances in defining memory T cell metabolism and how metabolism of these cells might be altered in patients affected by mitochondrial diseases or metabolic syndrome, who show higher susceptibility to recurrent infections and higher rates of vaccine failure. It discusses how this new understanding could add to the way we think about immunologic memory, vaccine development, and cancer immunotherapy.
    DOI:  https://doi.org/10.1172/JCI148546
  3. Cell Mol Immunol. 2022 Jan 04.
    Protein synthesis, degradation, and energy metabolism in T cell immunity.
    Julia M Marchingo, Doreen A Cantrell.
      T cell activation, proliferation, and differentiation into effector and memory states involve massive remodeling of T cell size and molecular content and create a massive increase in demand for energy and amino acids. Protein synthesis is an energy- and resource-demanding process; as such, changes in T cell energy production are intrinsically linked to proteome remodeling. In this review, we discuss how protein synthesis and degradation change over the course of a T cell immune response and the crosstalk between these processes and T cell energy metabolism. We highlight how the use of high-resolution mass spectrometry to analyze T cell proteomes can improve our understanding of how these processes are regulated.
    Keywords:  Immunometabolism; Protein Translation; Protein degradation; Proteomics; T lymphocyte
    DOI:  https://doi.org/10.1038/s41423-021-00792-8
  4. Trends Immunol. 2021 Dec 29. pii: S1471-4906(21)00262-3. [Epub ahead of print]
    Tumor microenvironment metabolites directing T cell differentiation and function.
    Xia Liu, Daniel F Hoft, Guangyong Peng.
      Metabolic reprogramming of cancer cells creates a unique tumor microenvironment (TME) characterized by the limited availability of nutrients, which subsequently affects the metabolism, differentiation, and function of tumor-infiltrating T lymphocytes (TILs). TILs can also be inhibited by tumor-derived metabolic waste products and low oxygen. Therefore, a thorough understanding of how such unique metabolites influence mammalian T cell differentiation and function can inform novel anticancer therapeutic approaches. Here, we highlight the importance of these metabolites in modulating various T cell subsets within the TME, dissecting how these changes might alter clinical outcomes. We explore potential TME metabolic determinants that might constitute candidate targets for cancer immunotherapies, ideally leading to future strategies for reprogramming tumor metabolism to potentiate anticancer T cell functions.
    Keywords:  T cells; metabolic reprogramming; metabolites; tumor immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.it.2021.12.004
  5. Diabetes. 2022 Jan 01. 71(1): 23-30
    Aging Leukocytes and the Inflammatory Microenvironment of the Adipose Tissue.
    Korbyn J V Dahlquist, Christina D Camell.
      Age-related immunosenescence, defined as an increase in inflammaging and the decline of the immune system, leads to tissue dysfunction and increased risk for metabolic disease. The elderly population is expanding, leading to a heightened need for therapeutics to improve health span. With age, many alterations of the immune system are observed, including shifts in the tissue-resident immune cells, increased expression of inflammatory factors, and the accumulation of senescent cells, all of which are responsible for a chronic inflammatory loop. Adipose tissue and the immune cell activation within are of particular interest for their well-known roles in metabolic disease. Recent literature reveals that adipose tissue is an organ in which signs of initial aging occur, including immune cell activation. Aged adipose tissue reveals changes in many innate and adaptive immune cell subsets, revealing a complex interaction that contributes to inflammation, increased senescence, impaired catecholamine-induced lipolysis, and impaired insulin sensitivity. Here, we will describe current knowledge surrounding age-related changes in immune cells while relating those findings to recent discoveries regarding immune cells in aged adipose tissue.
    DOI:  https://doi.org/10.2337/dbi21-0013
  6. Endocr Metab Immune Disord Drug Targets. 2022 Jan 04.
    Immunometabolism in bladder cancer microenvironment.
    Mohammad Javad Fattahi, Mohammad Reza Haghshenas, Abbas Ghaderi.
      The initiation and progression of bladder cancer (BC), is dependent on its tumor microenvironment (TME). On the other hand, cancer cells shape and train TME to support their development, respond to treatment and migration in an organism. Immune cells exert key roles in the BC microenvironment and have complex interactions with BC cells. These complicated interplays result in metabolic competition in the TME leading to nutrient deprivation, acidosis, hypoxia and metabolite accumulation, which impair immune cell function. Recent studies have demonstrated that immune cells functions are closely correlated with their metabolism. Immunometabolism describes the functional metabolic alterations that take place within immune cells and the role of these cells in directing metabolism and immune response in tissues or diseases such as cancer. Some molecules and their metabolites in the TME including glucose, fatty acids and amino acids can regulate the phenotype, function and metabolism of immune cells. Hence, here we describe some recent advances in immunometabolism and relate them to BC progression. A profound understanding of the metabolic reprogramming of BC cells and immune cells in the TME will offer novel opportunities for targeted therapies in future.
    Keywords:  Bladder cancer; Immunometabolism; Metabolic Reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.2174/1871530322666220104103905
  7. BMC Cancer. 2022 Jan 06. 22(1): 39
    Restricting tumor lactic acid metabolism using dichloroacetate improves T cell functions.
    Hosein Rostamian, Mohammad Khakpoor-Koosheh, Leila Jafarzadeh, Elham Masoumi, Keyvan Fallah-Mehrjardi, Mohammad Javad Tavassolifar, John M Pawelek, Hamid Reza Mirzaei, Jamshid Hadjati.
       BACKGROUND: Lactic acid produced by tumors has been shown to overcome immune surveillance, by suppressing the activation and function of T cells in the tumor microenvironment. The strategies employed to impair tumor cell glycolysis could improve immunosurveillance and tumor growth regulation. Dichloroacetate (DCA) limits the tumor-derived lactic acid by altering the cancer cell metabolism. In this study, the effects of lactic acid on the activation and function of T cells, were analyzed by assessing T cell proliferation, cytokine production and the cellular redox state of T cells. We examined the redox system in T cells by analyzing the intracellular level of reactive oxygen species (ROS), superoxide and glutathione and gene expression of some proteins that have a role in the redox system. Then we co-cultured DCA-treated tumor cells with T cells to examine the effect of reduced tumor-derived lactic acid on proliferative response, cytokine secretion and viability of T cells.
    RESULT: We found that lactic acid could dampen T cell function through suppression of T cell proliferation and cytokine production as well as restrain the redox system of T cells by decreasing the production of oxidant and antioxidant molecules. DCA decreased the concentration of tumor lactic acid by manipulating glucose metabolism in tumor cells. This led to increases in T cell proliferation and cytokine production and also rescued the T cells from apoptosis.
    CONCLUSION: Taken together, our results suggest accumulation of lactic acid in the tumor microenvironment restricts T cell responses and could prevent the success of T cell therapy. DCA supports anti-tumor responses of T cells by metabolic reprogramming of tumor cells.
    Keywords:  Cancer; Dichloroacetate, Immunotherapy; Lactic acid; Metabolism; T cell
    DOI:  https://doi.org/10.1186/s12885-021-09151-2
  8. Cell Metab. 2022 Jan 04. pii: S1550-4131(21)00622-7. [Epub ahead of print]34(1): 184-185
    Senescent immune cells release grancalcin to promote skeletal aging.
    Chang-Jun Li, Ye Xiao, Yu-Chen Sun, Wen-Zhen He, Ling Liu, Mei Huang, Chen He, Min Huang, Kai-Xuan Chen, Jing Hou, Xu Feng, Tian Su, Qi Guo, Yan Huang, Hui Peng, Mi Yang, Guang-Hui Liu, Xiang-Hang Luo.
      
    DOI:  https://doi.org/10.1016/j.cmet.2021.12.003
  9. Biol Reprod. 2022 Jan 04. pii: ioab241. [Epub ahead of print]
    Age-associated changes in cumulus cells and follicular fluid: The local oocyte microenvironment as a determinant of gamete quality.
    Elnur Babayev, Francesca E Duncan.
      The ovary is the first organ to age in humans with functional decline evident already in women in their early thirties. Reproductive aging is characterized by a decrease in oocyte quantity and quality which is associated with an increase in infertility, spontaneous abortions, and birth defects. Reproductive aging also has implications for overall health due to decreased endocrinological output. Understanding the mechanisms underlying reproductive aging has significant societal implications as women globally are delaying childbearing and medical interventions have greatly increased the interval between menopause and total lifespan. Age-related changes inherent to the female gamete are well-characterized and include defects in chromosome and mitochondria structure, function, and regulation. More recently, it has been appreciated that the extra-follicular ovarian environment may have important direct or indirect impacts on the developing gamete, and age-dependent changes include increased fibrosis, inflammation, stiffness, and oxidative damage. The cumulus cells and follicular fluid which directly surround the oocyte during its final growth phase within the antral follicle represent additional critical local microenvironments. Here we systematically review the literature and evaluate the studies that investigated the age-related changes in cumulus cells and follicular fluid. Our findings demonstrate unique genetic, epigenetic, transcriptomic, and proteomic changes with associated metabolomic alterations, redox status imbalance, and increased apoptosis in the local oocyte microenvironment. We propose a model of how these changes interact, which may explain the rapid decline in gamete quality with age. We also review the limitations of published studies and highlight future research frontiers.
    Keywords:  angiogenesis; apoptosis; epigenome; extracellular matrix; metabolism; mitochondrial DNA; proteome; reactive oxygen species; telomere; transcriptome
    DOI:  https://doi.org/10.1093/biolre/ioab241
  10. Cell Metab. 2022 Jan 04. pii: S1550-4131(21)00628-8. [Epub ahead of print]34(1): 106-124.e10
    A purine metabolic checkpoint that prevents autoimmunity and autoinflammation.
    Svetlana Saveljeva, Gavin W Sewell, Katharina Ramshorn, M Zaeem Cader, James A West, Simon Clare, Lea-Maxie Haag, Rodrigo Pereira de Almeida Rodrigues, Lukas W Unger, Ana Belén Iglesias-Romero, Lorraine M Holland, Christophe Bourges, Muhammad N Md-Ibrahim, James O Jones, Richard S Blumberg, James C Lee, Nicole C Kaneider, Trevor D Lawley, Allan Bradley, Gordon Dougan, Arthur Kaser.
      Still's disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of function of the purine nucleoside enzyme FAMIN is the sole known cause for monogenic Still's disease. Here we discovered that a FAMIN-enabled purine metabolon in dendritic cells (DCs) restrains CD4+ and CD8+ T cell priming. DCs with absent FAMIN activity prime for enhanced antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in excessive influenza A virus-specific responses. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ∼6% of mankind is homozygous. FAMIN controls membrane trafficking and restrains antigen presentation in an NADH/NAD+-dependent manner by balancing flux through adenine-guanine nucleotide interconversion cycles. FAMIN additionally converts hypoxanthine into inosine, which DCs release to dampen T cell activation. Compromised FAMIN consequently enhances immunosurveillance of syngeneic tumors. FAMIN is a biochemical checkpoint that protects against excessive antiviral T cell responses, autoimmunity, and autoinflammation.
    Keywords:  NADH/NAD(+) reductive stress; T cell priming; autoimmunity; dendritic cells; membrane trafficking; purine nucleotide cycle
    DOI:  https://doi.org/10.1016/j.cmet.2021.12.009
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