bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–04–02
eleven papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Decoding the crosstalk between mevalonate metabolism and T cell function.
  2. Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function.
  3. VMP1 prevents Ca2+ overload in endoplasmic reticulum and maintains naive T cell survival.
  4. Prostaglandin E 2 controls the metabolic adaptation of T cells to the intestinal microenvironment.
  5. T cell biomarkers come to the fore in cancer immunotherapy.
  6. 2-DG Re-Normalized IFN-γ Production in T Cells Excluding TEMRA Cells from Patients with Aplastic Anemia.
  7. IL-12 and IL-27 Promote CD39 Expression on CD8+ T Cells and Differentially Regulate the CD39+CD8+ T Cell Phenotype.
  8. Using mass spectrometry imaging to visualize age-related subcellular disruption.
  9. MicroRNA-124 Enhances T Cells Functions by Manipulating the Lactic Acid Metabolism of Tumor Cells.
  10. Clonal spreading of tumor-infiltrating T cells underlies the robust antitumor immune responses.
  11. Hematopoietic Stem Cells and the Immune System in Development and Aging.
  1. Immunol Rev. 2023 Mar 31.
    Decoding the crosstalk between mevalonate metabolism and T cell function.
    Kelly T Kennewick, Steven J Bensinger.
      The mevalonate pathway is an essential metabolic pathway in T cells regulating development, proliferation, survival, differentiation, and effector functions. The mevalonate pathway is a complex, branched pathway composed of many enzymes that ultimately generate cholesterol and nonsterol isoprenoids. T cells must tightly control metabolic flux through the branches of the mevalonate pathway to ensure sufficient isoprenoids and cholesterol are available to meet cellular demands. Unbalanced metabolite flux through the sterol or the nonsterol isoprenoid branch is metabolically inefficient and can have deleterious consequences for T cell fate and function. Accordingly, there is tight regulatory control over metabolic flux through the branches of this essential lipid synthetic pathway. In this review we provide an overview of how the branches of the mevalonate pathway are regulated in T cells and discuss our current understanding of the relationship between mevalonate metabolism, cholesterol homeostasis and T cell function.
    Keywords:  T cells; cholesterol; isoprenoids; mevalonate pathway; statins
    DOI:  https://doi.org/10.1111/imr.13200
  2. bioRxiv. 2023 Mar 15. pii: 2023.03.14.532663. [Epub ahead of print]
    Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function.
    Paul Renauer, Jonathan J Park, Meizhu Bai, Arianny Acosta, Won-Ho Lee, Guang Han Lin, Yueqi Zhang, Xiaoyun Dai, Guangchuan Wang, Youssef Errami, Terence Wu, Paul Clark, Lupeng Ye, Quanjun Yang, Sidi Chen.
      Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we seek to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism, whereby cancer cells suppress T cell function by generating a metabolically unfavorable tumor microenvironment (TME). Specifically, we use an in silico screen to identify ADA and PDK1 as metabolic regulators, in which gene overexpression (OE) enhances the cytolysis of CD19-specific CD8 CAR-T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampens such effect. ADA -OE in CAR-T cells improves cancer cytolysis under high concentrations of adenosine, the ADA substrate and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics in these CAR-Ts reveal alterations of global gene expression and metabolic signatures in both ADA- and PDK1- engineered CAR-T cells. Functional and immunological analyses demonstrate that ADA -OE increases proliferation and decreases exhaustion in α-CD19 and α-HER2 CAR-T cells. ADA-OE improves tumor infiltration and clearance by α-HER2 CAR-T cells in an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR-T cells, and reveal potential targets for improving CAR-T based cell therapy.
    Synopsis: The authors identify the adenosine deaminase gene (ADA) as a regulatory gene that reprograms T cell metabolism. ADA-overexpression (OE) in α-CD19 and α-HER2 CAR-T cells increases proliferation, cytotoxicity, memory, and decreases exhaustion, and ADA-OE α-HER2 CAR-T cells have enhanced clearance of HT29 human colorectal cancer tumors in vivo .
    DOI:  https://doi.org/10.1101/2023.03.14.532663
  3. J Exp Med. 2023 Jun 05. pii: e20221068. [Epub ahead of print]220(6):
    VMP1 prevents Ca2+ overload in endoplasmic reticulum and maintains naive T cell survival.
    Ying Liu, Yuying Ma, Jing Xu, Guangyue Zhang, Xiaocui Zhao, Zihao He, Lixia Wang, Na Yin, Min Peng.
      Ca2+ in endoplasmic reticulum (ER) dictates T cell activation, proliferation, and function via store-operated Ca2+ entry. How naive T cells maintain an appropriate level of Ca2+ in ER remains poorly understood. Here, we show that the ER transmembrane protein VMP1 is essential for maintaining ER Ca2+ homeostasis in naive T cells. VMP1 promotes Ca2+ release from ER under steady state, and its deficiency leads to ER Ca2+ overload, ER stress, and secondary Ca2+ overload in mitochondria, resulting in massive apoptosis of naive T cells and defective T cell response. Aspartic acid 272 (D272) of VMP1 is critical for its ER Ca2+ releasing activity, and a knockin mouse strain with D272 mutated to asparagine (D272N) demonstrates all functions of VMP1 in T cells in vivo depend on its regulation of ER Ca2+. These data uncover an indispensable role of VMP1 in preventing ER Ca2+ overload and maintaining naive T cell survival.
    DOI:  https://doi.org/10.1084/jem.20221068
  4. bioRxiv. 2023 Mar 15. pii: 2023.03.13.532431. [Epub ahead of print]
    Prostaglandin E 2 controls the metabolic adaptation of T cells to the intestinal microenvironment.
    Matteo Villa, David E Sanin, Petya Apostolova, Mauro Corrado, Agnieszka M Kabat, Carmine Cristinzio, Annamaria Regina, Gustavo E Carrizo, Nisha Rana, Michal A Stanczak, Francesc Baixauli, Katarzyna M Grzes, Jovana Cupovic, Francesca Solagna, Alexandra Hackl, Anna-Maria Globig, Fabian Hässler, Daniel J Puleston, Beth Kelly, Nina Cabezas-Wallscheid, Peter Hasselblatt, Bertram Bengsch, Robert Zeiser, Sagar, Joerg M Buescher, Edward J Pearce, Erika L Pearce.
      Immune cells must adapt to different environments during the course of an immune response. We studied the adaptation of CD8 + T cells to the intestinal microenvironment and how this process shapes their residency in the gut. CD8 + T cells progressively remodel their transcriptome and surface phenotype as they acquire gut residency, and downregulate expression of mitochondrial genes. Human and mouse gut-resident CD8 + T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We found that the intestinal microenvironment is rich in prostaglandin E 2 (PGE 2 ), which drives mitochondrial depolarization in CD8 + T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE 2 sensing promotes CD8 + T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell population. Thus, a PGE 2 -autophagy-glutathione axis defines the metabolic adaptation of CD8 + T cells to the intestinal microenvironment, to ultimately influence the T cell pool.
    DOI:  https://doi.org/10.1101/2023.03.13.532431
  5. Cell Rep Med. 2023 Mar 21. pii: S2666-3791(23)00095-2. [Epub ahead of print] 100989
    T cell biomarkers come to the fore in cancer immunotherapy.
    Lozan Sheriff, Alastair Copland, David Bending.
      A comprehensive study by van der Sluis et al.1 demonstrates immunotherapeutic targeting of OX40 and PD-L1 results in enhanced tumor clearance, which is linked to the dynamic emergence of distinct subsets of CD8+ T cells.
    DOI:  https://doi.org/10.1016/j.xcrm.2023.100989
  6. Immunol Invest. 2023 Mar 29. 1-15
    2-DG Re-Normalized IFN-γ Production in T Cells Excluding TEMRA Cells from Patients with Aplastic Anemia.
    Yue Zhang, Yuping Zhang, Xueqin Li, Xiaohui Chen, Yikai Zhang, Xiaoen Liu, Shujuan Wu, Yangqiu Li, Bo Li.
      Aplastic anemia (AA) is a T cell immune mediated autoimmune disease in which cytokines, particularly IFN-γ are pathogenesis factors. Glucose metabolism is closely related to effector functions of activated T cells, such as IFN-γ production. The characteristics of glucose metabolism and whether interfering with glucose metabolism could affect T cells produce IFN-γ ability in AA patients remains unknown. In this study, we examined the characteristics of glucose metabolism in T cells from AA patients and the effects of the glucose metabolism inhibitor 2-deoxy-D-glucose (2-DG) on the ability of T cell production IFN-γ. Our data demonstrated abnormal glucose metabolism in stimulated T cells from AA patients, mainly reflected by increased glucose uptake and lactate secretion. In addition, EM and TEMRA cells exhibit higher glucose uptake in patients with AA compared with healthy individuals. Moreover, the frequency of IFN-γ+ was reduced by 2-DG in T cell from AA patients. Unexpectedly, 2-DG re-normalized the frequency of IFN-γ+ in other T cell subsets, except for in the TEMRA. In conclusion, our study reveals for the first time the existence of enhanced aerobic glycolysis in T cells from AA patients, and different T cell subsets exhibit different extent glucose uptake requirements. Aerobic glycolysis regulation may be a potential therapeutic strategy for aberrant T cell immunity. Moreover, TEMRA may have specific metabolic abnormalities, which should receive more attention in future targeted immune metabolism research.
    Keywords:  2-deoxy-D-glucose; Aplastic anemia; effector memory cells re-expressing CD45RA cells; interferon γ
    DOI:  https://doi.org/10.1080/08820139.2023.2195436
  7. J Immunol. 2023 Mar 31. pii: ji2200897. [Epub ahead of print]
    IL-12 and IL-27 Promote CD39 Expression on CD8+ T Cells and Differentially Regulate the CD39+CD8+ T Cell Phenotype.
    Lara Gerhardt, Megan M Y Hong, Yeganeh Yousefi, Rene Figueredo, Saman Maleki Vareki.
      Tumor-specific CD8+ T cells are critical components of antitumor immunity; however, factors that modulate their phenotype and function have not been completely elucidated. Cytokines IL-12 and IL-27 have recognized roles in promoting CD8+ T cells' effector function and mediated antitumor responses. Tumor-specific CD8+ tumor-infiltrating lymphocytes (TILs) can be identified based on surface expression of CD39, whereas bystander CD8+ TILs do not express this enzyme. It is currently unclear how and why tumor-specific CD8+ T cells uniquely express CD39. Given the important roles of IL-12 and IL-27 in promoting CD8+ T cell functionality, we investigated whether these cytokines could modulate CD39 expression on these cells. Using in vitro stimulation assays, we identified that murine splenic CD8+ T cells differentially upregulate CD39 in the presence of IL-12 and IL-27. Subsequently, we assessed the exhaustion profile of IL-12- and IL-27-induced CD39+CD8+ T cells. Despite the greatest frequency of exhausted CD39+CD8+ T cells after activation with IL-12, as demonstrated by the coexpression of TIM-3+PD-1+LAG-3+ and reduced degranulation capacity, these cells retained the ability to produce IFN-γ. IL-27-induced CD39+CD8+ T cells expressed PD-1 but did not exhibit a terminally exhausted phenotype. IL-27 was able to attenuate IL-12-mediated inhibitory receptor expression on CD39+CD8+ T cells but did not rescue degranulation ability. Using an immunogenic neuro-2a mouse model, inhibiting IL-12 activity reduced CD39+CD8+ TIL frequency compared with controls without changing the overall CD8+ TIL frequency. These results provide insight into immune regulators of CD39 expression on CD8+ T cells and further highlight the differential impact of CD39-inducing factors on the phenotype and effector functions of CD8+ T cells.
    DOI:  https://doi.org/10.4049/jimmunol.2200897
  8. Front Mol Biosci. 2023 ;10 906606
    Using mass spectrometry imaging to visualize age-related subcellular disruption.
    Kelly A Hogan, Julianna D Zeidler, Heather K Beasley, Abrar I Alsaadi, Abdulkareem A Alshaheeb, Yi-Chin Chang, Hua Tian, Antentor O Hinton, Melanie R McReynolds.
      Metabolic homeostasis balances the production and consumption of energetic molecules to maintain active, healthy cells. Cellular stress, which disrupts metabolism and leads to the loss of cellular homeostasis, is important in age-related diseases. We focus here on the role of organelle dysfunction in age-related diseases, including the roles of energy deficiencies, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, changes in metabolic flux in aging (e.g., Ca2+ and nicotinamide adenine dinucleotide), and alterations in the endoplasmic reticulum-mitochondria contact sites that regulate the trafficking of metabolites. Tools for single-cell resolution of metabolite pools and metabolic flux in animal models of aging and age-related diseases are urgently needed. High-resolution mass spectrometry imaging (MSI) provides a revolutionary approach for capturing the metabolic states of individual cells and cellular interactions without the dissociation of tissues. mass spectrometry imaging can be a powerful tool to elucidate the role of stress-induced cellular dysfunction in aging.
    Keywords:  Golgi complex; MERCs; aging; mass spec imaging; metabolic flux; mitocchondrial dysfunction; spatial omics
    DOI:  https://doi.org/10.3389/fmolb.2023.906606
  9. Iran J Allergy Asthma Immunol. 2023 Feb 20. 22(1): 62-71
    MicroRNA-124 Enhances T Cells Functions by Manipulating the Lactic Acid Metabolism of Tumor Cells.
    Mohammad Khakpoor-Koosheh, Hosein Rostamian, Elham Masoumi, Leila Jafarzadeh, Keyvan Fallah-Mehrjardi, Mohammad Javad Tavassolifar, Farshid Noorbakhsh, Hamid Reza Mirzaei, Jamshid Hadjati, Nima Rezaei.
      High production of lactic acid is a common feature of various tumors. Lactic acid is an immunosuppressive molecule with crucial roles in tumor cells' immune escape, which could largely be attributed to its negative effects on the T cells present in the tumor microenvironment (TME). Strategies that decrease the glycolysis rate of tumor cells could enhance immunosurveillance and limit tumor growth. Pyruvate kinase M2 (PKM2) is a key enzyme in the glycolysis pathway, and it plays a vital role in lactic acid buildup in the TME. MicroRNA (miR)-124 has been shown to be able to decrease tumor cell lactic acid synthesis indirectly by reducing PKM2 levels. In this study, we first overexpressed miR-124 in the tumor cells and evaluated its effects on the PKM2 expression and lactic acid production of the tumor cells using quantitative real-time polymerase chain reaction (qRT-PCR) and spectrophotometry, respectively. Then, we cocultured miR-124-treated tumor cells with T cells to investigate the effects of miR-124 overexpression on T cell proliferation, cytokine production, and apoptosis. Our results demonstrated that miR-124 overexpression could significantly reduce the amount of lactic acid produced by tumor cells by manipulating their glucose metabolism, which led to the augmented proliferation and IFN-γ production of T cells. Moreover, it rescued T cells from lactic acid-induced apoptosis. Our data suggest that lactic acid is a hindering factor for T-cell-based immunotherapies; however, manipulating tumor cells' metabolism via miR-124 could be a promising way to improve antitumor responses of T cells.
    Keywords:  Lactic acid; MIRN124 microRNA, human; Metabolism; T-lymphocytes; Tumor microenvironment
    DOI:  https://doi.org/10.18502/ijaai.v22i1.12007
  10. Cancer Immunol Res. 2023 Mar 29. pii: CIR-22-0517. [Epub ahead of print]
    Clonal spreading of tumor-infiltrating T cells underlies the robust antitumor immune responses.
    Hiroyasu Aoki, Mikiya Tsunoda, Haru Ogiwara, Haruka Shimizu, Haruka Abe, Tatsuro Ogawa, Takaya Abe, Shigeyuki Shichino, Kouji Matsushima, Satoshi Ueha.
      The repertoire of tumor-infiltrating T cells is an emerging method for characterizing effective antitumor T-cell responses. Oligoclonal expansion of the tumor T-cell repertoire has been evaluated; however, their association with antitumor effects is unclear. We demonstrate here that the polyclonal fraction of the tumor-reactive T-cell repertoire, consisting of relatively minor clones, increased in tumor-bearing mice treated with monoclonal anti-PD-L1 or anti-CD4, which correlated with antitumor effects. Meanwhile, the size of the oligoclonal fraction consisting of major clones remained unchanged. Moreover, the polyclonal fraction was enriched in progenitor exhausted T cells, which are essential for a durable antitumor response, and was more dependent on CCR7+ migratory dendritic cells, which are responsible for priming tumor-reactive T cells in the tumor-draining lymph nodes. These results suggest that the expansion of diverse tumor-reactive clones ("clonal spreading") represents characteristics of antitumor T-cell responses induced by anti-CD4 and anti-PD-L1 treatment.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-22-0517
  11. Int J Mol Sci. 2023 Mar 20. pii: 5862. [Epub ahead of print]24(6):
    Hematopoietic Stem Cells and the Immune System in Development and Aging.
    Daniil Shevyrev, Valeriy Tereshchenko, Tatiana N Berezina, Stanislav Rybtsov.
      Hematopoietic stem cells (HSCs) support haematopoiesis throughout life and give rise to the whole variety of cells of the immune system. Developing in the early embryo, passing through the precursor stage, and maturing into the first HSCs, they undergo a fairly large number of divisions while maintaining a high regenerative potential due to high repair activity. This potential is greatly reduced in adult HSCs. They go into a state of dormancy and anaerobic metabolism to maintain their stemness throughout life. However, with age, changes occur in the pool of HSCs that negatively affect haematopoiesis and the effectiveness of immunity. Niche aging and accumulation of mutations with age reduces the ability of HSCs to self-renew and changes their differentiation potential. This is accompanied by a decrease in clonal diversity and a disturbance of lymphopoiesis (decrease in the formation of naive T- and B-cells) and the predominance of myeloid haematopoiesis. Aging also affects mature cells, regardless of HSC, therefore, phagocytic activity and the intensity of the oxidative burst decrease, and the efficiency of processing and presentation of antigens by myeloid cells is impaired. Aging cells of innate and adaptive immunity produce factors that form a chronic inflammatory background. All these processes have a serious negative impact on the protective properties of the immune system, increasing inflammation, the risk of developing autoimmune, oncological, and cardiovascular diseases with age. Understanding the mechanisms of reducing the regenerative potential in a comparative analysis of embryonic and aging HSCs, the features of inflammatory aging will allow us to get closer to deciphering the programs for the development, aging, regeneration and rejuvenation of HSCs and the immune system.
    Keywords:  HSC; HSC precursors; aging; aging biomarkers; haematopoietic clonality; haematopoietic hierarchy; hematopoietic stem cells; immune aging; immune senescence; inflammation; pre-HSC
    DOI:  https://doi.org/10.3390/ijms24065862
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