bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023‒10‒29
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. The glucose transporter 2 regulates CD8+ T cell function via environment sensing.
  2. Interferon-γ couples CD8+ T cell avidity and differentiation during infection.
  3. Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming.
  4. GLUT2, glucose and oxygen sensing in CD8+ T cells.
  5. Selective control of transposable element expression during T cell exhaustion and anti-PD-1 treatment.
  6. Lactate activates the mitochondrial electron transport chain independently of its metabolism.
  7. Research progress on CD8+ T cell immune regulation in allogenic transplantation.
  8. Reprogramming T cell differentiation and exhaustion in CAR-T cell therapy.
  9. CCR5 promotes the migration of CD8+ T cells to the leishmanial lesions.
  10. Immunosenescence and macrophages: From basics to therapeutics.
  11. Hematopoietic stem cells through the ages: A lifetime of adaptation to organismal demands.
  12. Hypoxia-responsive CAR-T cells exhibit reduced exhaustion and enhanced efficacy in solid tumors.
  13. The ticking of aging clocks.
  1. Nat Metab. 2023 Oct 26.
    The glucose transporter 2 regulates CD8+ T cell function via environment sensing.
    Hongmei Fu, Juho Vuononvirta, Silvia Fanti, Fabrizia Bonacina, Antonio D'Amati, Guosu Wang, Thanushiyan Poobalasingam, Maria Fankhaenel, Davide Lucchesi, Rachel Coleby, David Tarussio, Bernard Thorens, Robert J Hearnden, M Paula Longhi, Paul Grevitt, Madeeha H Sheikh, Egle Solito, Susana A Godinho, Michele Bombardieri, David M Smith, Dianne Cooper, Asif J Iqbal, Jeffrey C Rathmell, Samuel Schaefer, Valle Morales, Katiuscia Bianchi, Giuseppe Danilo Norata, Federica M Marelli-Berg.
      T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of effector function. Glucose uptake and engagement of the glycolytic pathway are major checkpoints for this event. Here we show that the low-affinity, concentration-dependent glucose transporter 2 (Glut2) regulates the development of CD8+ T cell effector responses in mice by promoting glucose uptake, glycolysis and glucose storage. Expression of Glut2 is modulated by environmental factors including glucose and oxygen availability and extracellular acidification. Glut2 is highly expressed by circulating, recently primed T cells, allowing efficient glucose uptake and storage. In glucose-deprived inflammatory environments, Glut2 becomes downregulated, thus preventing passive loss of intracellular glucose. Mechanistically, Glut2 expression is regulated by a combination of molecular interactions involving hypoxia-inducible factor-1 alpha, galectin-9 and stomatin. Finally, we show that human T cells also rely on this glucose transporter, thus providing a potential target for therapeutic immunomodulation.
    DOI:  https://doi.org/10.1038/s42255-023-00913-9
  2. Nat Commun. 2023 Oct 23. 14(1): 6727
    Interferon-γ couples CD8+ T cell avidity and differentiation during infection.
    Lion F K Uhl, Han Cai, Sophia L Oram, Jagdish N Mahale, Andrew J MacLean, Julie M Mazet, Theo Piccirilli, Alexander J He, Doreen Lau, Tim Elliott, Audrey Gerard.
      Effective responses to intracellular pathogens are characterized by T cell clones with a broad affinity range for their cognate peptide and diverse functional phenotypes. How T cell clones are selected throughout the response to retain a breadth of avidities remains unclear. Here, we demonstrate that direct sensing of the cytokine IFN-γ by CD8+ T cells coordinates avidity and differentiation during infection. IFN-γ promotes the expansion of low-avidity T cells, allowing them to overcome the selective advantage of high-avidity T cells, whilst reinforcing high-avidity T cell entry into the memory pool, thus reducing the average avidity of the primary response and increasing that of the memory response. IFN-γ in this context is mainly provided by virtual memory T cells, an antigen-inexperienced subset with memory features. Overall, we propose that IFN-γ and virtual memory T cells fulfil a critical immunoregulatory role by enabling the coordination of T cell avidity and fate.
    DOI:  https://doi.org/10.1038/s41467-023-42455-4
  3. Nat Commun. 2023 Oct 27. 14(1): 6858
    Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming.
    Hao Wu, Xiufeng Zhao, Sophia M Hochrein, Miriam Eckstein, Gabriela F Gubert, Konrad Knöpper, Ana Maria Mansilla, Arman Öner, Remi Doucet-Ladevèze, Werner Schmitz, Bart Ghesquière, Sebastian Theurich, Jan Dudek, Georg Gasteiger, Alma Zernecke, Sebastian Kobold, Wolfgang Kastenmüller, Martin Vaeth.
      T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-023-42634-3
  4. Nat Metab. 2023 Oct 26.
    GLUT2, glucose and oxygen sensing in CD8+ T cells.
    Xuemei Tong.
      
    DOI:  https://doi.org/10.1038/s42255-023-00914-8
  5. Sci Immunol. 2023 Oct 27. 8(88): eadf8838
    Selective control of transposable element expression during T cell exhaustion and anti-PD-1 treatment.
    Pierre-Emmanuel Bonté, Christina Metoikidou, Sandrine Heurtebise-Chretien, Yago A Arribas, Aurélien Sutra Del Galy, Mengliang Ye, Leticia Laura Niborski, Elina Zueva, Eliane Piaggio, Agathe Seguin-Givelet, Nicolas Girard, Cécile Alanio, Marianne Burbage, Christel Goudot, Sebastian Amigorena.
      In chronic infections and cancer, T cells are exposed to prolonged antigen stimulation, resulting in loss of function (or exhaustion) and impairment of effective immunological protection. Exhausted T cells are heterogeneous and include early progenitors (Tpex) and terminally exhausted cells (Tex). Here, we used bulk and single-cell transcriptomics to analyze expression of transposable elements (TEs) in subpopulations of mouse and human CD8+ tumor-infiltrating T lymphocytes (TILs). We show that in mice, members of the virus-like murine VL30 TE family (mostly intact, evolutionary young ERV1s) are strongly repressed in terminally exhausted CD8+ T cells in both tumor and viral models of exhaustion. Tpex expression of these VL30s, which are mainly intergenic and transcribed independently of their closest gene neighbors, was driven by Fli1, a transcription factor involved in progression from Tpex to Tex. Immune checkpoint blockade (ICB) in both mice and patients with cancer increased TE expression (including VL30 in mice), demonstrating that TEs may be applicable as ICB response biomarkers. We conclude that expression of TEs is tightly regulated in TILs during establishment of exhaustion and reprogramming by ICB. Analyses of TE expression on single cells and bulk populations open opportunities for understanding immune cell identity and heterogeneity, as well as for defining cellular gene expression signatures and disease biomarkers.
    DOI:  https://doi.org/10.1126/sciimmunol.adf8838
  6. Mol Cell. 2023 Oct 20. pii: S1097-2765(23)00800-6. [Epub ahead of print]
    Lactate activates the mitochondrial electron transport chain independently of its metabolism.
    Xin Cai, Charles P Ng, Olivia Jones, Tak Shun Fung, Keun Woo Ryu, Dayi Li, Craig B Thompson.
      Lactate has long been considered a cellular waste product. However, we found that as extracellular lactate accumulates, it also enters the mitochondrial matrix and stimulates mitochondrial electron transport chain (ETC) activity. The resulting increase in mitochondrial ATP synthesis suppresses glycolysis and increases the utilization of pyruvate and/or alternative respiratory substrates. The ability of lactate to increase oxidative phosphorylation does not depend on its metabolism. Both L- and D-lactate are effective at enhancing ETC activity and suppressing glycolysis. Furthermore, the selective induction of mitochondrial oxidative phosphorylation by unmetabolized D-lactate reversibly suppressed aerobic glycolysis in both cancer cell lines and proliferating primary cells in an ATP-dependent manner and enabled cell growth on respiratory-dependent bioenergetic substrates. In primary T cells, D-lactate enhanced cell proliferation and effector function. Together, these findings demonstrate that lactate is a critical regulator of the ability of mitochondrial oxidative phosphorylation to suppress glucose fermentation.
    Keywords:  TCA cycle; electron transport chain; glycolysis; lactate; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.034
  7. Transpl Immunol. 2023 Oct 21. pii: S0966-3274(23)00162-4. [Epub ahead of print]81 101945
    Research progress on CD8+ T cell immune regulation in allogenic transplantation.
    Haowen Jiang, Wenmei Fan.
      With advances in tissue typing, organ preservation techniques, and clinical surgery, organ transplantation has gained popularity as a treatment option for various end-stage diseases. Allogeneic transplantation has been widely adopted and extensively researched in clinical practice. Despite significant breakthroughs and progress in immunosuppression, this procedure is still associated with several adverse reactions and complications. Therefore, there is a continuing need to explore new immunological approaches to provide fresh insights and guidance for clinical transplantation. CD8+ T cells, traditionally known for their cytotoxic function and their ability to recognize transplanted organs as "non-self" entities, display cytotoxicity. However, recent studies have unveiled that CD8+ T cells have various subtypes and functions that extend beyond conventional cytotoxicity. These CD8+ T cell subtypes include Effector CD8+ T cells, Memory CD8+ T cells, and CD8Treg cells. This review examines the immune regulatory mechanisms of CD8+ T cells in allogeneic transplantation and discusses the potential applications of CD8+ T cells in treating tumors in transplant recipients who are receiving immunosuppressive therapy. These findings offer theoretical guidance for reducing post-transplant rejection reactions and improving adverse prognoses, offering new hope for improved clinical survival rate.
    Keywords:  Allogeneic transplantation; CD8+ T cells; CD8Treg cells; Complications; Effector CD8+ T cells; Memory CD8+ T cells
    DOI:  https://doi.org/10.1016/j.trim.2023.101945
  8. J Hematol Oncol. 2023 Oct 25. 16(1): 108
    Reprogramming T cell differentiation and exhaustion in CAR-T cell therapy.
    Yannick Bulliard, Borje S Andersson, Mehmet A Baysal, Jason Damiano, Apostolia M Tsimberidou.
      T cell differentiation is a highly regulated, multi-step process necessary for the progressive establishment of effector functions, immunological memory, and long-term control of pathogens. In response to strong stimulation, as seen in severe or chronic infections or cancer, T cells acquire a state of hypo-responsiveness known as exhaustion, limiting their effector function. Recent advances in autologous chimeric antigen receptor (CAR)-T cell therapies have revolutionized the treatment of hematologic malignancies by taking advantage of the basic principles of T cell biology to engineer products that promote long-lasting T cell response. However, many patients' malignancies remain unresponsive to treatment or are prone to recur. Discoveries in T cell biology, including the identification of key regulators of differentiation and exhaustion, offer novel opportunities to have a durable impact on the fate of CAR-T cells after infusion. Such next-generation CAR-T cell therapies and their clinical implementation may result in the next leap forward in cancer treatment for selected patients. In this context, this review summarizes the foundational principles of T cell differentiation and exhaustion and describes how they can be utilized and targeted to further improve the design and efficacy of CAR-T cell therapies.
    Keywords:  CAR-T; Differentiation; Exhaustion; Memory; T cell
    DOI:  https://doi.org/10.1186/s13045-023-01504-7
  9. bioRxiv. 2023 Oct 13. pii: 2023.10.10.561700. [Epub ahead of print]
    CCR5 promotes the migration of CD8+ T cells to the leishmanial lesions.
    Laís Amorim Sacramento, Camila Farias Amorim, Claudia G Lombana, Daniel Beiting, Fernanda Novais, Lucas P Carvalho, Edgar M Carvalho, Phillip Scott.
      Cytolytic CD8+ T cells mediate immunopathology in cutaneous leishmaniasis without controlling parasites. Here, we identify factors involved in CD8+ T cell migration to the lesion that could be targeted to ameliorate disease severity. CCR5 was the most highly expressed chemokine receptor in patient lesions, and the high expression of CCL3 and CCL4, CCR5 ligands, was associated with delayed healing of lesions. To test the requirement for CCR5, Leishmania-infected Rag1-/- mice were reconstituted with CCR5-/- CD8+ T cells. We found that these mice developed smaller lesions accompanied by a reduction in CD8+ T cell numbers compared to controls. We confirmed these findings by showing that the inhibition of CCR5 with maraviroc, a selective inhibitor of CCR5, reduced lesion development without affecting the parasite burden. Together, these results reveal that CD8+ T cells migrate to leishmanial lesions in a CCR5-dependent manner and that blocking CCR5 prevents CD8+ T cell-mediated pathology.
    Keywords:  CCR5; CD8 T cells; Leishmania braziliensis; cytotoxicity; immunopathology
    DOI:  https://doi.org/10.1101/2023.10.10.561700
  10. Int J Biochem Cell Biol. 2023 Oct 20. pii: S1357-2725(23)00118-8. [Epub ahead of print]165 106479
    Immunosenescence and macrophages: From basics to therapeutics.
    Hongkang Zhu, Fanglin Shen, Tingting Liao, He Qian, Yu Liu.
      Ageing decreases the function of the immune system and increases susceptibility to some chronic, infectious, and autoimmune diseases. Senescence cells, which produce senescence-associated secretory phenotypes (SASPs), can activate the innate and adaptive immune responses. Macrophages are among the most abundant innate immune cell types in senescent microenvironments. Senescence-associated macrophages, recruited by SASPs, play a vital role in establishing the essential microenvironments for maintaining tissue homeostasis. However, it's important to note that these senescence-associated macrophages can also influence senescent processes, either by enhancing or impeding the functions of tissue-resident senescent cells. In this discussion, we describe the potential targets of immunosenescence and shed light on the probable mechanisms by which macrophages influence cellular senescence. Furthermore, we analyze their dual function in both clearing senescent cells and modulating age-related diseases. This multifaceted influence operates through processes including heightened inflammation, phagocytosis, efferocytosis, and autophagy. Given the potential off-target effects and immune evasion mechanisms associated with traditional anti-ageing strategies (senolytics and senomorphics), 'resetting' immune system tolerance or targeting senescence-related macrophage functions (i.e., phagocytotic capacity and immunosurveillance) will inform treatment of age-related diseases. Therefore, we review recent advances in the use of macrophage therapeutics to treat ageing and age-associated disorders, and outline the key gaps in this field.
    Keywords:  Ageing; Macrophages; SASP; Senescent microenvironment; Therapeutics
    DOI:  https://doi.org/10.1016/j.biocel.2023.106479
  11. Cell Stem Cell. 2023 Oct 16. pii: S1934-5909(23)00360-0. [Epub ahead of print]
    Hematopoietic stem cells through the ages: A lifetime of adaptation to organismal demands.
    Monica Kasbekar, Carl A Mitchell, Melissa A Proven, Emmanuelle Passegué.
      Hematopoietic stem cells (HSCs), which govern the production of all blood lineages, transition through a series of functional states characterized by expansion during fetal development, functional quiescence in adulthood, and decline upon aging. We describe central features of HSC regulation during ontogeny to contextualize how adaptive responses over the life of the organism ultimately form the basis for HSC functional degradation with age. We particularly focus on the role of cell cycle regulation, inflammatory response pathways, epigenetic changes, and metabolic regulation. We then explore how the knowledge of age-related changes in HSC regulation can inform strategies for the rejuvenation of old HSCs.
    Keywords:  aging; development; epigenetic; hematopoietic stem cells; inflammation; metabolism; niche regulation; quiescence; rejuvenation
    DOI:  https://doi.org/10.1016/j.stem.2023.09.013
  12. Cancer Res. 2023 Oct 24.
    Hypoxia-responsive CAR-T cells exhibit reduced exhaustion and enhanced efficacy in solid tumors.
    Xiuxiu Zhu, Jun Chen, Wuling Li, Yanmin Xu, Juanjuan Shan, Juan Hong, Yongchun Zhao, Huailong Xu, Jiabing Ma, Junjie Shen, Cheng Qian.
      Expanding the utility of chimeric antigen receptor (CAR)-T cells in solid tumors requires improving their efficacy and safety. Hypoxia is a feature of most solid tumors that could be used to help CAR-T cells discriminate tumors from normal tissues. In this study, we developed hypoxia-responsive CAR-T cells by engineering the CAR to be under regulation of hypoxia responsive elements and selected the optimal structure (5H1P-CEA CAR), which can be activated in the tumor hypoxic microenvironment to induce CAR-T cells with high polyfunctionality. Hypoxia-responsive CAR-T cells were in a "resting" state with low CAR expression under normoxic conditions. Compared to conventional CAR-T cells, hypoxia-responsive CAR-T cells maintained lower differentiation and displayed enhanced oxidative metabolism and proliferation during cultivation, and they sowed a capacity to alleviate the negative effects of hypoxia on T cell proliferation and metabolism. Furthermore, 5H1P-CEA CAR-T cells exhibited decreased T cell exhaustion and improved T cell phenotype in vivo. In patient-derived xenograft models, hypoxia-responsive CAR-T cells induced more durable antitumor activity than their conventional counterparts. Overall, this study provides an approach to limit CAR expression to the hypoxic tumor microenvironment that could help to enhance CAR-T cell efficacy and safety in solid tumors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-1038
  13. Trends Endocrinol Metab. 2023 Oct 23. pii: S1043-2760(23)00196-0. [Epub ahead of print]
    The ticking of aging clocks.
    Jing-Dong J Han.
      Computational models that measure biological age and aging rate regardless of chronological age are called aging clocks. The underlying counting mechanisms of the intrinsic timers of these clocks are still unclear. Molecular mediators and determinants of aging rate point to the key roles of DNA damage, epigenetic drift, and inflammation. Persistent DNA damage leads to cellular senescence and the senescence-associated secretory phenotype (SASP), which induces cytotoxic immune cell infiltration; this further induces DNA damage through reactive oxygen and nitrogen species (RONS). I discuss the possibility that DNA damage (or the response to it, including epigenetic changes) is the fundamental counting unit of cell cycles and cellular senescence, that ultimately accounts for cell composition changes and functional decline in tissues, as well as the key intervention points.
    Keywords:  DNA damage; aging clock; counting unit; epigenetic regulation; metabolic coupling; senescence
    DOI:  https://doi.org/10.1016/j.tem.2023.09.007
This page is being maintained by Thomas Krichel. It was last updated on 2023‒10‒29 at 6:25.