bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–07–23
nine papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Mitochondria during T cell aging.
  2. TOX2 coordinates with TET2 to positively regulate central memory differentiation in human CAR T cells.
  3. Dietary restriction to optimize T cell immunity is an ancient survival strategy conserved in vertebrate evolution.
  4. A GPCR checkpoint drives CD8+ T cell dysfunction and immunotherapy failure in mice.
  5. The central role of DNA damage in immunosenescence.
  6. The mitochondrially targeted peptide elamipretide (SS-31) improves ADP sensitivity in aged mitochondria by increasing uptake through the adenine nucleotide translocator (ANT).
  7. Interplay between metabolic reprogramming and post-translational modifications: from glycolysis to lactylation.
  8. QUAS-R: An SLC1A5-mediated glutamine uptake assay with single-cell resolution reveals metabolic heterogeneity with immune populations.
  9. High-fat diet-disturbed gut microbiota-colonocyte interactions contribute to dysregulating peripheral tryptophan-kynurenine metabolism.
  1. Semin Immunol. 2023 Jul 18. pii: S1044-5323(23)00099-4. [Epub ahead of print]69 101808
    Mitochondria during T cell aging.
    Jose Ignacio Escrig-Larena, Sandra Delgado-Pulido, María Mittelbrunn.
      Mitochondrial dysfunction is a hallmark of aging that contributes to inflammaging. It is characterized by alterations of the mitochondrial DNA, reduced respiratory capacity, decreased mitochondrial membrane potential and increased reactive oxygen species production. These primary alterations disrupt other interconnected and important mitochondrial-related processes such as metabolism, mitochondrial dynamics and biogenesis, mitophagy, calcium homeostasis or apoptosis. In this review, we gather the current knowledge about the different mitochondrial processes which are altered during aging, with special focus on their contribution to age-associated T cell dysfunction and inflammaging.
    Keywords:  Aging; Apoptosis; Calcium homeostasis; Inflammaging; Lymphocyte; Mitochondria; Mitochondrial dynamics; Mitokines; Mitophagy; MtDNA; ROS; T cells
    DOI:  https://doi.org/10.1016/j.smim.2023.101808
  2. Sci Adv. 2023 Jul 21. 9(29): eadh2605
    TOX2 coordinates with TET2 to positively regulate central memory differentiation in human CAR T cells.
    Sierra M Collins, Katherine A Alexander, Stefan Lundh, Alexander J Dimitri, Zhen Zhang, Charly R Good, Joseph A Fraietta, Shelley L Berger.
      Chimeric antigen receptor (CAR) T cell therapy is used in treating human hematological malignancies, but its efficacy is limited by T cell exhaustion (TEX). TEX arises at the expense of central memory T cells (TCM), which exhibit robust antitumor efficacy. Reduction of the TET2 gene led to increased TCM differentiation in a patient with leukemia who experienced a complete remission. We show that loss of TET2 led to increased chromatin accessibility at exhaustion regulators TOX and TOX2, plus increased expression of TOX2. Knockdown of TOX increased the percentage of TCM. However, unexpectedly, knockdown of TOX2 decreased TCM percentage and reduced proliferation. Consistently, a TCM gene signature was reduced in the TOX2 knockdown, and TOX2 bound to promoters of numerous TCM genes. Our results thus suggest a role for human TOX2, in contrast to exhaustion regulator TOX, as a potentiator of central memory differentiation of CAR T cells, with plausible utility in CAR T cell cancer therapy via modulated TOX2 expression.
    DOI:  https://doi.org/10.1126/sciadv.adh2605
  3. Cell Mol Life Sci. 2023 Jul 20. 80(8): 219
    Dietary restriction to optimize T cell immunity is an ancient survival strategy conserved in vertebrate evolution.
    Kunming Li, Xiumei Wei, Kang Li, Qian Zhang, Jiansong Zhang, Ding Wang, Jialong Yang.
      Recent advances highlight a key role of transient fasting in optimizing immunity of human and mouse. However, it remains unknown whether this strategy is independently acquired by mammals during evolution or instead represents gradually evolved functions common to vertebrates. Using a tilapia model, we report that T cells are the main executors of the response of the immune system to fasting and that dietary restriction bidirectionally modulates T cell immunity. Long-term fasting impaired T cell immunity by inducing intense autophagy, apoptosis, and aberrant inflammation. However, transient dietary restriction triggered moderate autophagy to optimize T cell response by maintaining homeostasis, alleviating inflammation and tissue damage, as well as enhancing T cell activation, proliferation and function. Furthermore, AMPK is the central hub linking fasting and autophagy-controlled T cell immunity in tilapia. Our findings demonstrate that dietary restriction to optimize immunity is an ancient strategy conserved in vertebrate evolution, providing novel perspectives for understanding the adaptive evolution of T cell response.
    Keywords:  Autophagy; Dietary restriction; Evolution; T cells; Tilapia
    DOI:  https://doi.org/10.1007/s00018-023-04865-x
  4. Nat Immunol. 2023 Jul 17.
    A GPCR checkpoint drives CD8+ T cell dysfunction and immunotherapy failure in mice.
      
    DOI:  https://doi.org/10.1038/s41590-023-01567-1
  5. Front Aging. 2023 ;4 1202152
    The central role of DNA damage in immunosenescence.
    Loren Kell, Anna Katharina Simon, Ghada Alsaleh, Lynne S Cox.
      Ageing is the biggest risk factor for the development of multiple chronic diseases as well as increased infection susceptibility and severity of diseases such as influenza and COVID-19. This increased disease risk is linked to changes in immune function during ageing termed immunosenescence. Age-related loss of immune function, particularly in adaptive responses against pathogens and immunosurveillance against cancer, is accompanied by a paradoxical gain of function of some aspects of immunity such as elevated inflammation and increased incidence of autoimmunity. Of the many factors that contribute to immunosenescence, DNA damage is emerging as a key candidate. In this review, we discuss the evidence supporting the hypothesis that DNA damage may be a central driver of immunosenescence through senescence of both immune cells and cells of non-haematopoietic lineages. We explore why DNA damage accumulates during ageing in a major cell type, T cells, and how this may drive age-related immune dysfunction. We further propose that existing immunosenescence interventions may act, at least in part, by mitigating DNA damage and restoring DNA repair processes (which we term "genoprotection"). As such, we propose additional treatments on the basis of their evidence for genoprotection, and further suggest that this approach may provide a viable therapeutic strategy for improving immunity in older people.
    Keywords:  DNA damage; DNA repair; ageing; immunology; immunosenescence; senescence
    DOI:  https://doi.org/10.3389/fragi.2023.1202152
  6. Geroscience. 2023 Jul 18.
    The mitochondrially targeted peptide elamipretide (SS-31) improves ADP sensitivity in aged mitochondria by increasing uptake through the adenine nucleotide translocator (ANT).
    Gavin Pharaoh, Varun Kamat, Sricharan Kannan, Rudolph S Stuppard, Jeremy Whitson, Miguel Martín-Pérez, Wei-Jun Qian, Michael J MacCoss, Judit Villén, Peter Rabinovitch, Matthew D Campbell, Ian R Sweet, David J Marcinek.
      Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment, in vivo heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function. ELAM binds directly to ANT and ATP synthase and ELAM treatment improves ADP sensitivity, increases ATP production, and improves physiological function in old muscles. ADP (adenosine diphosphate), ATP (adenosine triphosphate), VDAC (voltage-dependent anion channel), ANT (adenine nucleotide translocator), H+ (proton), ROS (reactive oxygen species), NADH (nicotinamide adenine dinucleotide), FADH2 (flavin adenine dinucleotide), O2 (oxygen), ELAM (elamipretide), -SH (free thiol), -SSG (glutathionylated protein).
    Keywords:  ATP production; Adenine nucleotide translocator (ANT); Adenosine diphosphate (ADP) sensitivity; Elamipretide or SS-31; Mitochondrial dysfunction; Oxygen consumption rate (OCR)
    DOI:  https://doi.org/10.1007/s11357-023-00861-y
  7. Front Immunol. 2023 ;14 1211221
    Interplay between metabolic reprogramming and post-translational modifications: from glycolysis to lactylation.
    Hengwei Wu, He Huang, Yanmin Zhao.
      Cellular metabolism plays a critical role in determining the fate and function of cells. Metabolic reprogramming and its byproducts have a complex impact on cellular activities. In quiescent T cells, oxidative phosphorylation (OXPHOS) is the primary pathway for survival. However, upon antigen activation, T cells undergo rapid metabolic reprogramming, characterized by an elevation in both glycolysis and OXPHOS. While both pathways are induced, the balance predominantly shifts towards glycolysis, enabling T cells to rapidly proliferate and enhance their functionality, representing the most distinctive signature during activation. Metabolic processes generate various small molecules resulting from enzyme-catalyzed reactions, which also modulate protein function and exert regulatory control. Notably, recent studies have revealed the direct modification of histones, known as lactylation, by lactate derived from glycolysis. This lactylation process influences gene transcription and adds a novel variable to the regulation of gene expression. Protein lactylation has been identified as an essential mechanism by which lactate exerts its diverse functions, contributing to crucial biological processes such as uterine remodeling, tumor proliferation, neural system regulation, and metabolic regulation. This review focuses on the metabolic reprogramming of T cells, explores the interplay between lactate and the immune system, highlights the impact of lactylation on cellular function, and elucidates the intersection of metabolic reprogramming and epigenetics.
    Keywords:  epigenetics; glycolysis; lactate; lactylation; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2023.1211221
  8. Cell Rep. 2023 Jul 19. pii: S2211-1247(23)00839-2. [Epub ahead of print]42(8): 112828
    QUAS-R: An SLC1A5-mediated glutamine uptake assay with single-cell resolution reveals metabolic heterogeneity with immune populations.
    Leonard R Pelgrom, Gavin M Davis, Simon O'Shaughnessy, Emilie J M Wezenberg, Sander I Van Kasteren, David K Finlay, Linda V Sinclair.
      System-level analysis of single-cell data is rapidly transforming the field of immunometabolism. Given the competitive demand for nutrients in immune microenvironments, there is a need to understand how and when immune cells access these nutrients. Here, we describe a new approach for single-cell analysis of nutrient uptake where we use in-cell biorthogonal labeling of a functionalized amino acid after transport into the cell. In this manner, the bona fide active uptake of glutamine via SLC1A5/ASCT2 could be quantified. We used this assay to interrogate the transport capacity of complex immune subpopulations, both in vitro and in vivo. Taken together, our findings provide an easy sensitive single-cell assay to assess which cells support their function via SLC1A5-mediated uptake. This is a significant addition to the single-cell metabolic toolbox required to decode the metabolic landscape of complex immune microenvironments.
    Keywords:  CP: Immunology; CP: Metabolism; SLC1A5; amino acid transport; glutamine uptake; lymphocytes
    DOI:  https://doi.org/10.1016/j.celrep.2023.112828
  9. Microbiome. 2023 Jul 19. 11(1): 154
    High-fat diet-disturbed gut microbiota-colonocyte interactions contribute to dysregulating peripheral tryptophan-kynurenine metabolism.
    Penghao Sun, Mengli Wang, Yong-Xin Liu, Luqi Li, Xuejun Chai, Wei Zheng, Shulin Chen, Xiaoyan Zhu, Shanting Zhao.
       BACKGROUND: Aberrant tryptophan (Trp)-kynurenine (Kyn) metabolism has been implicated in the pathogenesis of human disease. In particular, populations with long-term western-style diets are characterized by an excess of Kyn in the plasma. Host-gut microbiota interactions are dominated by diet and are essential for maintaining host metabolic homeostasis. However, the role of western diet-disturbed gut microbiota-colonocyte interactions in Trp metabolism remains to be elucidated.
    RESULTS: Here, 4-week-old mice were fed with a high-fat diet (HFD), representing a typical western diet, for 4 weeks, and multi-omics approaches were adopted to determine the mechanism by which HFD disrupted gut microbiota-colonocyte interplay causing serum Trp-Kyn metabolism dysfunction. Our results showed that colonocyte-microbiota interactions dominated the peripheral Kyn pathway in HFD mice. Mechanistically, persistent HFD-impaired mitochondrial bioenergetics increased colonic epithelial oxygenation and caused metabolic reprogramming in colonites to support the expansion of Proteobacteria in the colon lumen. Phylum Proteobacteria-derived lipopolysaccharide (LPS) stimulated colonic immune responses to upregulate the indoleamine 2,3-dioxygenase 1 (IDO1)-mediated Kyn pathway, leading to Trp depletion and Kyn accumulation in the circulation, which was further confirmed by transplantation of Escherichia coli (E.coli) indicator strains and colonic IDO1 depletion. Butyrate supplementation promoted mitochondrial functions in colonocytes to remodel the gut microbiota in HFD mice, consequently ameliorating serum Kyn accumulation.
    CONCLUSIONS: Our results highlighted that HFD disrupted the peripheral Kyn pathway in a gut microbiota-dependent manner and that the continuous homeostasis of gut bacteria-colonocytes interplay played a central role in the regulation of host peripheral Trp metabolism. Meanwhile, this study provided new insights into therapies against western diet-related metabolic disorders. Video Abstract.
    Keywords:  Gut microbiota; High-fat diet; Kynurenine; Mitochondrial dysfunction; Tryptophan metabolism
    DOI:  https://doi.org/10.1186/s40168-023-01606-x
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