bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–06–25
nine papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Differential Effects of Glutamine Inhibition Strategies on Antitumor CD8 T Cells.
  2. 13 C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 + T cells.
  3. Cell metabolism-based optimization strategy of CAR-T cell function in cancer therapy.
  4. Interleukin-27 potentiates CD8+ T-cell-mediated anti-tumor immunity in chronic lymphocytic leukemia.
  5. Deletion of enzymes for de novo NAD+ biosynthesis accelerated ovarian aging.
  6. T cells in health and disease.
  7. Redox signaling in impaired cascades of wound healing: promising approach.
  8. Editorial: Mitochondrial bioenergetics impairments in genetic and metabolic diseases.
  9. Human circulating and tissue-resident memory CD8+ T cells.
  1. J Immunol. 2023 Jun 21. pii: ji2200715. [Epub ahead of print]
    Differential Effects of Glutamine Inhibition Strategies on Antitumor CD8 T Cells.
    Matthew Z Madden, Xiang Ye, Channing Chi, Emilie L Fisher, Melissa M Wolf, Gabriel A Needle, Jackie E Bader, Andrew R Patterson, Bradley I Reinfeld, Madelyn D Landis, Emma S Hathaway, Jason E Muka, Richard T O'Neil, John Karijolich, Mary Philip, Jeffrey C Rathmell.
      Activated T cells undergo metabolic reprogramming to meet anabolic, differentiation, and functional demands. Glutamine supports many processes in activated T cells, and inhibition of glutamine metabolism alters T cell function in autoimmune disease and cancer. Multiple glutamine-targeting molecules are under investigation, yet the precise mechanisms of glutamine-dependent CD8 T cell differentiation remain unclear. We show that distinct strategies of glutamine inhibition by glutaminase-specific inhibition with small molecule CB-839, pan-glutamine inhibition with 6-diazo-5-oxo-l-norleucine (DON), or by glutamine-depleted conditions (No Q) produce distinct metabolic differentiation trajectories in murine CD8 T cells. T cell activation with CB-839 treatment had a milder effect than did DON or No Q treatment. A key difference was that CB-839-treated cells compensated with increased glycolytic metabolism, whereas DON and No Q-treated cells increased oxidative metabolism. However, all glutamine treatment strategies elevated CD8 T cell dependence on glucose metabolism, and No Q treatment caused adaptation toward reduced glutamine dependence. DON treatment reduced histone modifications and numbers of persisting cells in adoptive transfer studies, but those T cells that remained could expand normally upon secondary Ag encounter. In contrast, No Q-treated cells persisted well yet demonstrated decreased secondary expansion. Consistent with reduced persistence, CD8 T cells activated in the presence of DON had reduced ability to control tumor growth and reduced tumor infiltration in adoptive cell therapy. Overall, each approach to inhibit glutamine metabolism confers distinct effects on CD8 T cells and highlights that targeting the same pathway in different ways can elicit opposing metabolic and functional outcomes.
    DOI:  https://doi.org/10.4049/jimmunol.2200715
  2. bioRxiv. 2023 Jun 11. pii: 2023.06.09.544407. [Epub ahead of print]
    13 C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 + T cells.
    Eric H Ma, Michael S Dahabieh, Lisa M DeCamp, Irem Kaymak, Susan M Kitchen-Goosen, Dominic G Roy, Mark J Verway, Radia M Johnson, Bozena Samborska, Catherine A Scullion, Mya Steadman, Matthew Vos, Thomas P Roddy, Connie M Krawczyk, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.
      Infusion of 13C-labeled metabolites provides a gold-standard for understanding the metabolic processes used by T cells during immune responses in vivo . Through infusion of 13C-labeled metabolites (glucose, glutamine, acetate) in Listeria monocytogenes ( Lm )-infected mice, we demonstrate that CD8+ T effector (Teff) cells utilize metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily towards nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support ATP and de novo pyrimidine synthesis. Additionally, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)-which regulates de novo aspartate synthesis-for effector cell expansion in vivo . Importantly, Teff cells change fuel preference over the course of infection, switching from glutamine-to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with Teff cell function in vivo .
    Teaser: Interrogating dynamics of fuel utilization by CD8 + T cells in vivo reveals new metabolic checkpoints for immune function in vivo .
    DOI:  https://doi.org/10.1101/2023.06.09.544407
  3. Front Immunol. 2023 ;14 1186383
    Cell metabolism-based optimization strategy of CAR-T cell function in cancer therapy.
    Wenshuai Li, Xuanxuan Pan, Lirong Chen, Haoshu Cui, Shaocong Mo, Yida Pan, Yuru Shen, Menglin Shi, Jianlin Wu, Feifei Luo, Jie Liu, Na Li.
      Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR)-modified T cells has revolutionized the field of immune-oncology, showing remarkable efficacy against hematological malignancies. However, its success in solid tumors is limited by factors such as easy recurrence and poor efficacy. The effector function and persistence of CAR-T cells are critical to the success of therapy and are modulated by metabolic and nutrient-sensing mechanisms. Moreover, the immunosuppressive tumor microenvironment (TME), characterized by acidity, hypoxia, nutrient depletion, and metabolite accumulation caused by the high metabolic demands of tumor cells, can lead to T cell "exhaustion" and compromise the efficacy of CAR-T cells. In this review, we outline the metabolic characteristics of T cells at different stages of differentiation and summarize how these metabolic programs may be disrupted in the TME. We also discuss potential metabolic approaches to improve the efficacy and persistence of CAR-T cells, providing a new strategy for the clinical application of CAR-T cell therapy.
    Keywords:  CAR (chimeric antigen receptor) T cells; cancer therapy; cell metabolism; immunity therapy; optimization strategy
    DOI:  https://doi.org/10.3389/fimmu.2023.1186383
  4. Haematologica. 2023 Jun 22.
    Interleukin-27 potentiates CD8+ T-cell-mediated anti-tumor immunity in chronic lymphocytic leukemia.
    Giulia Pagano, Iria Fernandez Botana, Marina Wierz, Philipp M Roessner, Nikolaos Ioannou, Xiangda Zhou, Gheed Al-Hity, Coralie Borne, Ernesto Gargiulo, Susanne Gonder, Bin Qu, Basile Stamatopoulos, Alan G Ramsay, Martina Seiffert, Anne Largeot, Etienne Moussay, Jerome Paggetti.
      Chronic Lymphocytic Leukemia (CLL) cells are highly dependent on interactions with the immunosuppressive tumor microenvironment (TME) for survival and proliferation. In the search for novel treatments, pro-inflammatory cytokines have emerged as candidates to reactivate the immune system. Among those, IL-27 has recently gained attention, but its effects differ among malignancies. Here, we utilized the Eμ-TCL1 and EBI3 knock-out mouse models as well as clinical samples from patients to investigate the role of IL-27 in CLL. Characterization of murine leukemic spleens revealed that the absence of IL-27 leads to enhanced CLL development and a more immunosuppressive TME in transgenic mice. Gene-profiling of T-cell subsets from EBI3 knock-out highlighted transcriptional changes in the CD8+ T-cell population associated with T-cell activation, proliferation, and cytotoxicity. We also observed an increased anti-tumor activity of CD8+ T cells in presence of IL-27 ex vivo with murine and clinical samples. Notably, IL-27 treatment led to the reactivation of autologous T cells from CLL patients. Finally, we detected a decrease in IL-27 serum levels during CLL development in both pre-clinical and patient samples. Altogether, we demonstrated that IL-27 has a strong antitumorigenic role in CLL and postulate this cytokine as a promising treatment or adjuvant for this malignancy.
    DOI:  https://doi.org/10.3324/haematol.2022.282474
  5. Aging Cell. 2023 Jun 18. e13904
    Deletion of enzymes for de novo NAD+ biosynthesis accelerated ovarian aging.
    Qingling Yang, Hui Li, Huan Wang, Wenhui Chen, Xinxin Zeng, Xiaoyan Luo, Jianmin Xu, Yingpu Sun.
      Recent advances highlight the pivotal role of nicotinamide adenine dinucleotide (NAD+ ) in ovarian aging. However, the roles of de novo NAD+ biosynthesis on ovarian aging are still unknown. Here, we found that genetic ablation of Ido1 (indoleamine-2,3-dioxygenase 1) or Qprt (Quinolinate phosphoribosyl transferase), two critical genes in de novo NAD+ biosynthesis, resulted in decreased ovarian NAD+ levels in middle-aged mice, leading to subfertility, irregular estrous cycles, reduced ovarian reserve, and accelerated aging. Moreover, we observed impaired oocyte quality, characterized by increased reactive oxygen species and spindle anomalies, which ultimately led to reduced fertilization ability and impaired early embryonic development. A transcriptomic analysis of ovaries in both mutant and wild-type mice revealed alterations in gene expression related to mitochondrial metabolism. Our findings were further supported by the observation of impaired mitochondrial distribution and decreased mitochondrial membrane potential in the oocytes of knockout mice. Supplementation with nicotinamide riboside (NR), an NAD+ booster, in mutant mice increased ovarian reserve and improved oocyte quality. Our study highlights the importance of the NAD+ de novo pathway in middle-aged female fertility.
    Keywords:  de novo NAD+ synthesis pathway; mitochondrial function; ovarian aging; reactive oxygen species
    DOI:  https://doi.org/10.1111/acel.13904
  6. Signal Transduct Target Ther. 2023 Jun 19. 8(1): 235
    T cells in health and disease.
    Lina Sun, Yanhong Su, Anjun Jiao, Xin Wang, Baojun Zhang.
      T cells are crucial for immune functions to maintain health and prevent disease. T cell development occurs in a stepwise process in the thymus and mainly generates CD4+ and CD8+ T cell subsets. Upon antigen stimulation, naïve T cells differentiate into CD4+ helper and CD8+ cytotoxic effector and memory cells, mediating direct killing, diverse immune regulatory function, and long-term protection. In response to acute and chronic infections and tumors, T cells adopt distinct differentiation trajectories and develop into a range of heterogeneous populations with various phenotype, differentiation potential, and functionality under precise and elaborate regulations of transcriptional and epigenetic programs. Abnormal T-cell immunity can initiate and promote the pathogenesis of autoimmune diseases. In this review, we summarize the current understanding of T cell development, CD4+ and CD8+ T cell classification, and differentiation in physiological settings. We further elaborate the heterogeneity, differentiation, functionality, and regulation network of CD4+ and CD8+ T cells in infectious disease, chronic infection and tumor, and autoimmune disease, highlighting the exhausted CD8+ T cell differentiation trajectory, CD4+ T cell helper function, T cell contributions to immunotherapy and autoimmune pathogenesis. We also discuss the development and function of γδ T cells in tissue surveillance, infection, and tumor immunity. Finally, we summarized current T-cell-based immunotherapies in both cancer and autoimmune diseases, with an emphasis on their clinical applications. A better understanding of T cell immunity provides insight into developing novel prophylactic and therapeutic strategies in human diseases.
    DOI:  https://doi.org/10.1038/s41392-023-01471-y
  7. Mol Biol Rep. 2023 Jun 21.
    Redox signaling in impaired cascades of wound healing: promising approach.
    Mehmet Can Atayik, Ufuk Çakatay.
      In the aging communities, wound healing management is a quite remarkable problem especially in elderly individuals. The optimal level of healing of wounds developed spontaneously or due to surgery is of critical importance in order to prevent the negative effects that may occur due to delayed healing (for example, organ or system damage caused by infections that may develop in the wound area). The deteriorated subcellular redox signaling is considered to be as the main factor in the chronicity of wounds. The pivotal role of mitochondria in redox regulation reveals the importance of modulation of redox signaling pathways in senescent cells. Secretory factors released upon the acquisition of senescence-associated secretory phenotype (SASP) function in a paracrine manner to disseminate impaired tissue redox status by affecting the redox metabolome of nearby cells, which could promote age-related pro-inflammatory pathologies. Evaluating the wound-site redox regulation in impaired redox signaling pathways may help prevent the formation of chronic wounds and the development of long-term complications of the wounds, especially in the elderly. Using the redox modulatory pharmacologically active substances targeting the senescent cells in chronic wound areas hopefully opens a new avenue in wound management. As the signaling mechanisms of wound healing and its relationship with advanced age become more clearly understood, many promising therapeutic approaches and redox modulator substances are coming into clinical view for the management of chronic wounds.
    Keywords:  Aging; Chronic wounds; Redox signaling; Senescence-associated secretory phenotype; Therapeutic approaches; Wound healing
    DOI:  https://doi.org/10.1007/s11033-023-08589-w
  8. Front Physiol. 2023 ;14 1228926
    Editorial: Mitochondrial bioenergetics impairments in genetic and metabolic diseases.
    Christian Bergamini, Elena Bonora, Noah Moruzzi.
      
    Keywords:  bioenergetics; inherited human disorders; metabolic impairment; mitochondria; mitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fphys.2023.1228926
  9. Nat Immunol. 2023 Jun 22.
    Human circulating and tissue-resident memory CD8+ T cells.
    Marcus Buggert, David A Price, Laura K Mackay, Michael R Betts.
      Our current knowledge of human memory CD8+ T cells is derived largely from studies of the intravascular space. However, emerging data are starting to challenge some of the dogmas based on this work, suggesting that a conceptual revision may be necessary. In this review, we provide a brief history of the field and summarize the biology of circulating and tissue-resident memory CD8+ T cells, which are ultimately responsible for effective immune surveillance. We also incorporate recent findings into a biologically integrated model of human memory CD8+ T cell differentiation. Finally, we address how future innovative human studies could improve our understanding of anatomically localized CD8+ T cells to inform the development of more effective immunotherapies and vaccines, the need for which has been emphasized by the global struggle to contain severe acute respiratory syndrome coronavirus 2.
    DOI:  https://doi.org/10.1038/s41590-023-01538-6
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