bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–05–14
eleven papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Inosine Induces Stemness Features in CAR T cells and Enhances Potency.
  2. Role of T cells in the pathogenesis of systemic lupus erythematous: Focus on immunometabolism dysfunctions.
  3. Chemical inhibition of DNA-PKcs impairs the activation and cytotoxicity of CD4+ helper and CD8+ effector T cells.
  4. Editorial: Molecular crosstalk between endocrine factors, paracrine signals, and the immune system during aging.
  5. Lipid metabolism in dendritic cell biology.
  6. The short-chain fatty acid acetate coordinates with CD30 to modulate T cell survival.
  7. Aging accelerates the tempo of transcription.
  8. Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy.
  9. A single-cell atlas of the aging murine ovary.
  10. Vaccine boosts T cells that target pancreatic tumours.
  11. Age-mediated gut microbiota dysbiosis promotes the loss of dendritic cells tolerance.
  1. bioRxiv. 2023 Apr 25. pii: 2023.04.21.537859. [Epub ahead of print]
    Inosine Induces Stemness Features in CAR T cells and Enhances Potency.
    Dorota D Klysz, Carley Fowler, Meena Malipatlolla, Lucille Stuani, Katherine A Freitas, Stefanie Meier, Bence Daniel, Katalin Sandor, Peng Xu, Jing Huang, Louai Labanieh, Amaury Leruste, Malek Bashti, Vimal Keerthi, Janette Mata-Alcazar, Nikolaos Gkitsas, Justin A Guerrero, Chris Fisher, Sunny Patel, Kyle Asano, Shabnum Patel, Kara L Davis, Ansuman T Satpathy, Steven A Feldman, Elena Sotillo, Crystal L Mackall.
      Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8 + CAR T cells mediate Ado-induced immunosuppression through CD39/73-dependent Ado production. Knockout of CD39, CD73 or A2aR had modest effects on exhausted CAR T cells, whereas overexpression of Ado deaminase (ADA), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced functionality. Similarly, and to a greater extent, exposure of CAR T cells to INO augmented CAR T cell function and induced hallmark features of T cell stemness. INO induced a profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and modulated the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR T cell products meeting criteria for clinical dosing. These data identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.
    Statement of Significance: Adenosine is well known to inhibit T cell function and substantial effort has focused on inhibiting adenosine generation and signaling. Here, we show that exhausted T cells are suppressed by adenosine, which is only modestly impacted by inhibiting adenosine generation or signaling. In contrast, metabolism of adenosine to inosine augmented T cell function and culture of T cells with inosine induced multi-level reprogramming leading to stemness and improved anti-tumor potency. We demonstrate the feasibility of introducing inosine during GMP cell manufacturing as a novel strategy to generate enhanced CAR-T cells.
    DOI:  https://doi.org/10.1101/2023.04.21.537859
  2. Int Immunopharmacol. 2023 May 04. pii: S1567-5769(23)00567-2. [Epub ahead of print]119 110246
    Role of T cells in the pathogenesis of systemic lupus erythematous: Focus on immunometabolism dysfunctions.
    Mohamed J Saadh, Khadijehsadat Kazemi, Hossein Khorramdelazad, Mohammad Javad Mousavi, Negar Noroozi, Maryam Masoumi, Jafar Karami.
      Evidence demonstrates that T cells are implicated in developing SLE, and each of them dominantly uses distinct metabolic pathways. Indeed, intracellular enzymes and availability of specific nutrients orchestrate fate of T cells and lead to differentiation of regulatory T cells (Treg), memory T cells, helper T cells, and effector T cells. The function of T cells in inflammatory and autoimmune responses is determined by metabolic processes and activity of their enzymes. Several studies were conducted to determine metabolic abnormalities in SLE patients and clarify how these modifications could control the functions of the involved T cells. Metabolic pathways such as glycolysis, mitochondrial pathways, oxidative stress, mTOR pathway, fatty acid and amino acid metabolisms are dysregulated in SLE T cells. Moreover, immunosuppressive drugs used in treating autoimmune diseases, including SLE, could affect immunometabolism. Developing drugs to regulate autoreactive T cell metabolism could be a promising therapeutic approach for SLE treatment. Accordingly, increased knowledge about metabolic processes paves the way to understanding SLE pathogenesis better and introduces novel therapeutic options for SLE treatment. Although monotherapy with metabolic pathways modulators might not be sufficient to prevent autoimmune disease, they may be an ideal adjuvant to reduce administration doses of immunosuppressive drugs, thus reducing drug-associated adverse effects. This review summarized emerging data about T cells that are involved in SLE pathogenesis, focusing on immunometabolism dysregulation and how these modifications could affect the disease development.
    Keywords:  Autoimmunity; Immunometabolism; SLE T cell; Systemic lupus erythematous
    DOI:  https://doi.org/10.1016/j.intimp.2023.110246
  3. Immunol Cell Biol. 2023 May 06.
    Chemical inhibition of DNA-PKcs impairs the activation and cytotoxicity of CD4+ helper and CD8+ effector T cells.
    Ana C Azevedo-Pouly, Lauren E Appell, Lyle Burdine, Lora J Rogers, Lauren C Morehead, Daniel Fil, Melanie Barker, Randall R Rainwater, Zachary J Waldrip, Brian Koss, Marie Schluterman Burdine.
      Modulation of T cell activity is an effective strategy for the treatment of autoimmune diseases, immune-related disorders and cancer. This highlights a critical need for the identification of proteins that regulate T cell function. The kinase DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is emerging as a potent regulator of the immune system, spurring interest in its use as a therapeutic target. In murine models of immune-related diseases including asthma and rheumatoid arthritis, treatment with small-molecule DNA-PKcs inhibitors decreased the disease severity. Additionally, DNA-PKcs inhibitors reduced T cell-mediated graft rejection in a murine allogenic skin graft model. These in vivo studies suggest the use of DNA-PKcs inhibitors as immunotherapy for autoimmune and T cell-mediated disorders. In this study, we sought to characterize further the effects of DNA-PKcs inhibitors on T cells to better understand their clinical potential. We determined that inhibition of DNA-PKcs using inhibitor NU7441 and the inhibitors currently in clinical trials for cancer therapy, M3184 and AZD7648, abrogated the activation of murine and human CD4+ and CD8+ T cells as evidenced by the reduced expression of the activation markers CD69 and CD25. Furthermore, inhibition of DNA-PKcs impeded metabolic pathways and the proliferation of activated T cells. This reduced the ability of OTI-CD8+ T cells to kill cancer cells and the expression of IFNγ and cytotoxic genes. These results highlight a critical role for DNA-PKcs in T cells and validate future studies using DNA-PKcs inhibitors as immune modulation therapy for the treatment of immune-related diseases.
    Keywords:  CD4+ helper T cells; CD8+ effector T cells; DNA dependent protein kinase catalytic subunit; NU7441T cell activation; OTISIINFEKL-MC38; T cell metabolism; cytotoxicity
    DOI:  https://doi.org/10.1111/imcb.12651
  4. Front Endocrinol (Lausanne). 2023 ;14 1203755
    Editorial: Molecular crosstalk between endocrine factors, paracrine signals, and the immune system during aging.
    Durai Sellegounder, Luigi Ferrucci, Rajakumar Anbazhagan, Nathan Basisty.
      
    Keywords:  aging; endocrinology; hormones; immune system; metabolism & endocrinology; paracrine signal; senescence
    DOI:  https://doi.org/10.3389/fendo.2023.1203755
  5. Immunol Rev. 2023 May 12.
    Lipid metabolism in dendritic cell biology.
    Zhiyuan You, Hongbo Chi.
      Dendritic cells (DCs) are innate immune cells that detect and process environmental signals and communicate them with T cells to bridge innate and adaptive immunity. Immune signals and microenvironmental cues shape the function of DC subsets in different contexts, which is associated with reprogramming of cellular metabolic pathways. In addition to integrating these extracellular cues to meet bioenergetic and biosynthetic demands, cellular metabolism interplays with immune signaling to shape DC-dependent immune responses. Emerging evidence indicates that lipid metabolism serves as a key regulator of DC responses. Here, we summarize the roles of fatty acid and cholesterol metabolism, as well as selective metabolites, in orchestrating the functions of DCs. Specifically, we highlight how different lipid metabolic programs, including de novo fatty acid synthesis, fatty acid β oxidation, lipid storage, and cholesterol efflux, influence DC function in different contexts. Further, we discuss how dysregulation of lipid metabolism shapes DC intracellular signaling and contributes to the impaired DC function in the tumor microenvironment. Finally, we conclude with a discussion on key future directions for the regulation of DC biology by lipid metabolism. Insights into the connections between lipid metabolism and DC functional specialization may facilitate the development of new therapeutic strategies for human diseases.
    Keywords:  cholesterol; dendritic cells; fatty acid; innate immunity; lipid metabolism; lipid metabolites
    DOI:  https://doi.org/10.1111/imr.13215
  6. Mol Biol Cell. 2023 May 10. mbcE23010032
    The short-chain fatty acid acetate coordinates with CD30 to modulate T cell survival.
    Junfang Lyu, Ziyi Li, Jessica Roberts, Yue A Qi, Jianhua Xiong.
      As an important substrate for cell metabolism, the short-chain fatty acid acetate emerges as a regulator of cell fate and function. However, its role in T cell survival and its underlying mechanisms remain largely unknown. Here, we demonstrate that acetate modulates T cell apoptosis via potentiation of α-tubulin acetylation. We further show that acetate treatment effectively increases the expression of the tumor necrosis factor receptor (TNFR) family member CD30 by enhancing its gene transcription. Moreover, CD30 physically associates with and stabilizes the deacetylase HDAC6, which deacetylates α-tubulin to decrease microtubule stability. Proteomic profiling of Cd30 knockout (Cd30-/-) T cells reveals elevated expression of anti-apoptotic BCL2 family proteins and thus promotes T cell survival via a microtubule-Bcl-2 axis. Taken together, our results demonstrate that acetate is a regulator of T cell survival by controlling levels of acetylated α-tubulin. This suggests that therapeutic manipulation of acetate metabolism may facilitate optimal T cell responses in pathological conditions.
    DOI:  https://doi.org/10.1091/mbc.E23-01-0032
  7. Nat Aging. 2023 May 08.
    Aging accelerates the tempo of transcription.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-023-00423-z
  8. Elife. 2023 May 11. pii: e84280. [Epub ahead of print]12
    Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy.
    Pedro P Cunha, Eleanor Minogue, Lena C M Krause, Rita M Hess, David Bargiela, Brennan J Wadsworth, Laura Barbieri, Carolin Brombach, Iosifina P Foskolou, Ivan Bogeski, Pedro Velica, Randall S Johnson.
      Oxygenation levels are a determinative factor in T cell function. Here we describe that the oxygen tensions sensed by mouse and human T cells at the moment of activation act to persistently modulate both differentiation and function. We found that in a protocol of CAR-T cell generation, 24 hours of low oxygen levels during initial CD8+ T cell priming is sufficient to enhance antitumour cytotoxicity in a preclinical model. This is the case even when CAR-T cells are subsequently cultured under high oxygen tensions prior to adoptive transfer. Increased hypoxia inducible transcription factor (HIF) expression was able to alter T cell fate in a similar manner to exposure to low oxygen tensions; however, only a controlled or temporary increase in HIF signalling was able to consistently improve cytotoxic function of T cells. These data show that oxygenation levels during and immediately after T cell activation play an essential role in regulating T cell function.
    Keywords:  human; immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.84280
  9. bioRxiv. 2023 Apr 29. pii: 2023.04.29.538828. [Epub ahead of print]
    A single-cell atlas of the aging murine ovary.
    José V V Isola, Sarah R Ocañas, Chase R Hubbart, Sunghwan Ko, Samim Ali Mondal, Jessica D Hense, Augusto Schneider, Susan Kovats, Willard M Freeman, Michael B Stout.
      Ovarian aging leads to diminished fertility, dysregulated endocrine signaling, and increased chronic disease burden. These effects begin to emerge long before follicular exhaustion. Around 35 years old, women experience a sharp decline in fertility, corresponding to declines in oocyte quality. However, the field lacks a cellular map of the transcriptomic changes in the aging ovary to identify drivers of ovarian decline. To fill this gap, we performed single-cell RNA sequencing on ovarian tissue from young (3-month-old) and reproductively aged (9-month-old) mice. Our analysis revealed a doubling of immune cells in the aged ovary, with T and B lymphocyte proportions increasing most. We also discovered an age-related upregulation of alternative macrophage and downregulation of collagenase pathways in stromal fibroblasts. Overall, follicular cells (especially granulosa and theca) display stress response, immunogenic, and fibrotic signaling pathway inductions with aging. These changes are more exaggerated in the atretic granulosa cells but are also observed in healthy antral and preantral granulosa cells. Moreover, we did not observe age-related changes in markers of cellular senescence in any cellular population with advancing age, despite specific immune cells expressing senescence-related genes across both timepoints. This report raises several new hypotheses that could be pursued to elucidate mechanisms responsible for ovarian aging phenotypes.
    DOI:  https://doi.org/10.1101/2023.04.29.538828
  10. Nature. 2023 May 10.
    Vaccine boosts T cells that target pancreatic tumours.
    Amanda L Huff, Neeha Zaidi.
      
    Keywords:  Cancer; Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-023-01526-8
  11. Aging Cell. 2023 May 09. e13838
    Age-mediated gut microbiota dysbiosis promotes the loss of dendritic cells tolerance.
    Hilal Bashir, Sanpreet Singh, Raghwendra Pratap Singh, Javed N Agrewala, Rashmi Kumar.
      The old age-related loss of immune tolerance inflicts a person with a wide range of autoimmune and inflammatory diseases. Dendritic cells (DCs) are the sentinels of the immune system that maintain immune tolerance through cytokines and regulatory T-cells generation. Aging disturbs the microbial composition of the gut, causing immune system dysregulation. However, the vis-à-vis role of gut dysbiosis on DCs tolerance remains highly elusive. Consequently, we studied the influence of aging on gut dysbiosis and its impact on the loss of DC tolerance. We show that DCs generated from either the aged (DCOld ) or gut-dysbiotic young (DCDysbiotic ) but not young (DCYoung ) mice exhibited loss of tolerance, as evidenced by their failure to optimally induce the generation of Tregs and control the overactivation of CD4+ T cells. The mechanism deciphered for the loss of DCOld and DCDysbiotic tolerance was chiefly through the overactivation of NF-κB, impaired frequency of Tregs, upregulation in the level of pro-inflammatory molecules (IL-6, IL-1β, TNF-α, IL-12, IFN-γ), and decline in the anti-inflammatory moieties (IL-10, TGF-β, IL-4, IDO, arginase, NO, IRF-4, IRF-8, PDL1, BTLA4, ALDH2). Importantly, a significant decline in the frequency of the Lactobacillus genus was noticed in the gut. Replenishing the gut of old mice with the Lactobacillus plantarum reinvigorated the tolerogenic function of DCs through the rewiring of inflammatory and metabolic pathways. Thus, for the first time, we demonstrate the impact of age-related gut dysbiosis on the loss of DC tolerance. This finding may open avenues for therapeutic intervention for treating age-associated disorders with the Lactobacillus plantarum.
    Keywords:  aging; dendritic cells; dysbiosis; gut microbiota; immune response; tolerance
    DOI:  https://doi.org/10.1111/acel.13838
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