bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024‒05‒26
twelve papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

  1. Cytotherapy. 2024 May 01. pii: S1465-3249(24)00684-4. [Epub ahead of print]
      BACKGROUND AIMS: Vγ9Vδ2 T cells are under investigation as alternative effector cells for adoptive cell therapy (ACT) in cancer. Despite promising in vitro results, anti-tumor efficacies in early clinical studies have been lower than expected, which could be ascribed to the complex interplay of tumor and immune cell metabolism competing for the same nutrients in the tumor microenvironment.METHODS: To contribute to the scarce knowledge regarding gamma delta T-cell metabolism, we investigated the metabolic phenotype of 25-day-expanded Vγ9Vδ2 T cells and how it is intertwined with functionality.
    RESULTS: We found that Vγ9Vδ2 T cells displayed a quiescent metabolism, utilizing both glycolysis and oxidative phosphorylation (OXPHOS) for energy production, as measured in Seahorse assays. Upon T-cell receptor activation, both pathways were upregulated, and inhibition with metabolic inhibitors showed that Vγ9Vδ2 T cells were dependent on glycolysis and the pentose phosphate pathway for proliferation. The dependency on glucose for proliferation was confirmed in glucose-free conditions. Cytotoxicity against malignant melanoma was reduced by glycolysis inhibition but not OXPHOS inhibition.
    CONCLUSIONS: These findings lay the groundwork for further studies on manipulation of Vγ9Vδ2 T-cell metabolism for improved ACT outcome.
    Keywords:  Vγ9Vδ2 T cells; adoptive cell therapy; cytotoxicity; glycolysis; metabolism; γδ T cells
  2. Res Sq. 2024 May 07. pii: [Epub ahead of print]
      Activated T cells undergo a metabolic shift to aerobic glycolysis to support the energetic demands of proliferation, differentiation, and cytolytic function. Transmembrane glucose flux is facilitated by glucose transporters (GLUT) that play a vital role in T cell metabolic reprogramming and anti-tumour function. GLUT isoforms are regulated at the level of expression and subcellular distribution. GLUTs also display preferential selectivity for carbohydrate macronutrients including glucose, galactose, and fructose. GLUT5, which selectively transports fructose over glucose, has never been explored as a genetic engineering strategy to enhance CAR-T cells in fructose-rich tumour environments. Fructose levels are significantly elevated in the bone marrow and the plasma of acute myeloid leukaemia (AML) patients. Here, we demonstrate that the expression of wild-type GLUT5 restores T cell metabolic fitness in glucose-free, high fructose conditions. We find that fructose supports maximal glycolytic capacity and ATP replenishment rates in GLUT5-expressing T cells. Using steady state tracer technology, we show that 13C6 fructose supports glycolytic reprogramming and TCA anaplerosis in CAR-T cells undergoing log phase expansion. In cytotoxicity assays, GLUT5 rescues T cell cytolytic function in glucose-free medium. The fructose/GLUT5 metabolic axis also supports maximal migratory velocity, which provides mechanistic insight into why GLUT5-expressing CAR-Ts have superior effector function as they undergo "hit-and-run" serial killing. These findings translate to superior anti-tumour function in a xenograft model of AML. In fact, we found that GLUT5 enhances CAR-T cell anti-tumour function in vivo without any need for fructose intervention. Accordingly, we hypothesize that GLUT5 is sufficient to enhance CAR-T resilience by increasing the cells' competitiveness for glucose at physiologic metabolite levels. Our findings have immediate translational relevance by providing the first evidence that GLUT5 confers a competitive edge in a fructose-enriched milieu, and is a novel approach to overcome glucose depletion in hostile tumour microenvironments (TMEs).
  3. Trends Immunol. 2024 May 22. pii: S1471-4906(24)00100-5. [Epub ahead of print]
      Activated CD8+ T cells directly kill target cells. Therefore, the regulation of their function is central to avoiding immunopathology. Mechanisms that curb effector functions in CD4+ and CD8+ T cells are mostly shared, yet important differences occur. Here, we focus on the control of CD8+ T cell activity and discuss the importance of a poorly understood aspect of tolerance that directly impairs engagement of target cells: the downregulation of CD8. We contextualize this process and propose that it represents a key element during CD8+ T cell modulation.
    Keywords:  CD8; double negative T cell; tolerance
  4. JCI Insight. 2024 May 22. pii: e177054. [Epub ahead of print]9(10):
      Redundant tumor microenvironment (TME) immunosuppressive mechanisms and epigenetic maintenance of terminal T cell exhaustion greatly hinder functional antitumor immune responses in chronic lymphocytic leukemia (CLL). Bromodomain and extraterminal (BET) proteins regulate key pathways contributing to CLL pathogenesis and TME interactions, including T cell function and differentiation. Herein, we report that blocking BET protein function alleviates immunosuppressive networks in the CLL TME and repairs inherent CLL T cell defects. The pan-BET inhibitor OPN-51107 reduced exhaustion-associated cell signatures resulting in improved T cell proliferation and effector function in the Eμ-TCL1 splenic TME. Following BET inhibition (BET-i), TME T cells coexpressed significantly fewer inhibitory receptors (IRs) (e.g., PD-1, CD160, CD244, LAG3, VISTA). Complementary results were witnessed in primary CLL cultures, wherein OPN-51107 exerted proinflammatory effects on T cells, regardless of leukemic cell burden. BET-i additionally promotes a progenitor T cell phenotype through reduced expression of transcription factors that maintain terminal differentiation and increased expression of TCF-1, at least in part through altered chromatin accessibility. Moreover, direct T cell effects of BET-i were unmatched by common targeted therapies in CLL. This study demonstrates the immunomodulatory action of BET-i on CLL T cells and supports the inclusion of BET inhibitors in the management of CLL to alleviate terminal T cell dysfunction and potentially enhance tumoricidal T cell activity.
    Keywords:  Drug therapy; Immunology; Leukemias; Oncology; T cells
  5. Nat Commun. 2024 May 24. 15(1): 4444
      Mitochondrial respiration is essential for the survival and function of T cells used in adoptive cellular therapies. However, strategies that specifically enhance mitochondrial respiration to promote T cell function remain limited. Here, we investigate methylation-controlled J protein (MCJ), an endogenous negative regulator of mitochondrial complex I expressed in CD8 cells, as a target for improving the efficacy of adoptive T cell therapies. We demonstrate that MCJ inhibits mitochondrial respiration in murine CD8+ CAR-T cells and that deletion of MCJ increases their in vitro and in vivo efficacy against murine B cell leukaemia. Similarly, MCJ deletion in ovalbumin (OVA)-specific CD8+ T cells also increases their efficacy against established OVA-expressing melanoma tumors in vivo. Furthermore, we show for the first time that MCJ is expressed in human CD8 cells and that the level of MCJ expression correlates with the functional activity of CD8+ CAR-T cells. Silencing MCJ expression in human CD8 CAR-T cells increases their mitochondrial metabolism and enhances their anti-tumor activity. Thus, targeting MCJ may represent a potential therapeutic strategy to increase mitochondrial metabolism and improve the efficacy of adoptive T cell therapies.
  6. JCI Insight. 2024 May 21. pii: e176381. [Epub ahead of print]
      Alloreactive memory, unlike naïve, CD8+ T cells resist transplantation tolerance protocols and are a critical barrier to long-term graft acceptance in the clinic. We here show that semi-allogeneic pregnancy successfully reprogrammed memory fetus/graft-specific CD8+ T cells (TFGS) towards hypofunction. Female C57BL/6 mice harboring memory CD8+ T cells generated by the rejection of BALB/c skin grafts and then mated with BALB/c males achieved rates of pregnancy comparable to naive controls. Post-partum fetus/graft-specific CD8+ T cells (TFGS) from skin-sensitized dams upregulated expression of T cell exhaustion (TEX) markers (Tox, Eomes, PD-1, TIGIT, and Lag3). Transcriptional analysis corroborated an enrichment of canonical T exhaustion (TEX) genes in post-partum memory TFGS and additionally, revealed a downregulation of a subset of memory-associated transcripts. Strikingly, pregnancy induced extensive epigenetic modifications of exhaustion- and memory-associated genes in memory TFGS, whereas minimal epigenetic modifications were observed in naive TFGS cells. Finally, post-partum memory TFGS durably expressed the exhaustion-enriched phenotype, and their susceptibility to transplantation tolerance was significantly restored compared to memory TFGS. These findings advance the concept of pregnancy as an epigenetic modulator inducing hypofunction in memory CD8+ T cells that has relevance not only for pregnancy and transplantation tolerance, but also for tumor immunity and chronic infections.
    Keywords:  Bioinformatics; Immunology; T cells; Transplantation
  7. Trends Genet. 2024 May 22. pii: S0168-9525(24)00099-4. [Epub ahead of print]
      Intimate links between epigenome modifications and metabolites allude to a crucial role of cellular metabolism in transcriptional regulation. Retina, being a highly metabolic tissue, adapts by integrating inputs from genetic, epigenetic, and extracellular signals. Precise global epigenomic signatures guide development and homeostasis of the intricate retinal structure and function. Epigenomic and metabolic realignment are hallmarks of aging and highlight a link of the epigenome-metabolism nexus with aging-associated multifactorial traits affecting the retina, including age-related macular degeneration and glaucoma. Here, we focus on emerging principles of epigenomic and metabolic control of retinal gene regulation, with emphasis on their contribution to human disease. In addition, we discuss potential mitigation strategies involving lifestyle changes that target the epigenome-metabolome relationship for maintaining retinal function.
    Keywords:  DNA methylation; age-related macular degeneration; diet; environmental factors; gene regulation; histone modifications; metabolic pathways; multifactorial traits; vision impairment
  8. Cell Discov. 2024 May 20. 10(1): 53
      Peripheral CD8+ T cell number is tightly controlled but the precise molecular mechanism regulating this process is still not fully understood. In this study, we found that epilepsy patients with loss of function mutation of DEPDC5 had reduced peripheral CD8+ T cells, and DEPDC5 expression positively correlated with tumor-infiltrating CD8+ T cells as well as overall cancer patient survival, indicating that DEPDC5 may control peripheral CD8+ T cell homeostasis. Significantly, mice with T cell-specific Depdc5 deletion also had reduced peripheral CD8+ T cells and impaired anti-tumor immunity. Mechanistically, Depdc5-deficient CD8+ T cells produced high levels of xanthine oxidase and lipid ROS due to hyper-mTORC1-induced expression of ATF4, leading to spontaneous ferroptosis. Together, our study links DEPDC5-mediated mTORC1 signaling with CD8+ T cell protection from ferroptosis, thereby revealing a novel strategy for enhancing anti-tumor immunity via suppression of ferroptosis.
  9. Cell Commun Signal. 2024 May 24. 22(1): 285
      Aging is a complex and multifaceted process involving a variety of interrelated molecular mechanisms and cellular systems. Phenotypically, the biological aging process is accompanied by a gradual loss of cellular function and the systemic deterioration of multiple tissues, resulting in susceptibility to aging-related diseases. Emerging evidence suggests that aging is closely associated with telomere attrition, DNA damage, mitochondrial dysfunction, loss of nicotinamide adenine dinucleotide levels, impaired macro-autophagy, stem cell exhaustion, inflammation, loss of protein balance, deregulated nutrient sensing, altered intercellular communication, and dysbiosis. These age-related changes may be alleviated by intervention strategies, such as calorie restriction, improved sleep quality, enhanced physical activity, and targeted longevity genes. In this review, we summarise the key historical progress in the exploration of important causes of aging and anti-aging strategies in recent decades, which provides a basis for further understanding of the reversibility of aging phenotypes, the application prospect of synthetic biotechnology in anti-aging therapy is also prospected.
    Keywords:  Aging; Aging triggers; Anti-aging strategies; Senolytic; Synthetic
  10. Small. 2024 May 22. e2400598
      Advanced age is a major risk factor for age-related degenerative tendinopathy. During aging, tendon stem/progenitor cell (TSPC) function declines owing to the transition from a normal quiescent state to a senescent state. Extracellular vesicles (EVs) from young stem cells are reported to possess anti-aging functions. However, it remains unclear whether EVs from young TSPCs (TSPC-EVs) can rejuvenate senescent TSPCs to delay age-related degeneration. Here, this study finds that TSPC-EVs can mitigate the aging phenotypes of senescent TSPCs and maintain their tenogenic capacity. In vitro studies reveal that TSPC-EVs can reinstall autophagy in senescent TSPCs to alleviate cellular senescence, and that the re-establishment of autophagy is mediated by the PI3K/AKT pathway. Mechanistically, this study finds that thrombospondin 1, a negative regulator of the PI3K/AKT pathway, is enriched in TSPC-EVs and can be transported to senescent TSPCs. Moreover, in vivo studies show that the local delivery of TSPC-EVs can rejuvenate senescent TSPCs and promote their tenogenic differentiation, thereby rescuing tendon regeneration in aged rats. Taken together, TSPC-EVs as a novel cell-free approach have promising therapeutic potential for aging-related degenerative tendinopathy.
    Keywords:  age‐related degenerative tendinopathy; autophagy; cellular senescence; extracellular vesicles; tendon stem/progenitor cells
  11. Nutrients. 2024 May 13. pii: 1470. [Epub ahead of print]16(10):
      As women age, oocytes are susceptible to a myriad of dysfunctions, including mitochondrial dysfunction, impaired DNA repair mechanisms, epigenetic alterations, and metabolic disturbances, culminating in reduced fertility rates among older individuals. Ferredoxin (FDX) represents a highly conserved iron-sulfur (Fe-S) protein essential for electron transport across multiple metabolic pathways. Mammalian mitochondria house two distinct ferredoxins, FDX1 and FDX2, which share structural similarities and yet perform unique functions. In our investigation into the regulatory mechanisms governing ovarian aging, we employed a comprehensive multi-omics analysis approach, integrating spatial transcriptomics, single-cell RNA sequencing, human ovarian pathology, and clinical biopsy data. Previous studies have highlighted intricate interactions involving excessive lipid peroxide accumulation, redox-induced metal ion buildup, and alterations in cellular energy metabolism observed in aging cells. Through a multi-omics analysis, we observed a notable decline in the expression of the critical gene FDX1 as ovarian age progressed. This observation prompted speculation regarding FDX1's potential as a promising biomarker for ovarian aging. Following this, we initiated a clinical trial involving 70 patients with aging ovaries. These patients were administered oral nutritional supplements consisting of DHEA, ubiquinol CoQ10, and Cleo-20 T3 for a period of two months to evaluate alterations in energy metabolism regulated by FDX1. Our results demonstrated a significant elevation in FDX1 levels among participants receiving nutritional supplementation. We hypothesize that these nutrients potentiate mitochondrial tricarboxylic acid cycle (TCA) activity or electron transport chain (ETC) efficiency, thereby augmenting FDX1 expression, an essential electron carrier in metabolic pathways, while concurrently mitigating lipid peroxide accumulation and cellular apoptosis. In summary, our findings underscore the potential of nutritional intervention to enhance in vitro fertilization outcomes in senescent cells by bolstering electron transport proteins, thus optimizing energy metabolism and improving oocyte quality in aging women.
    Keywords:  FDX1; multi-omics; nutrients; ovarian aging
  12. Immunol Rev. 2024 May 20.
      Obesity presents a significant health challenge, affecting 41% of adults and 19.7% of children in the United States. One of the associated health challenges of obesity is chronic low-grade inflammation. In both mice and humans, T cells in circulation and in the adipose tissue play a pivotal role in obesity-associated inflammation. Changes in the numbers and frequency of specific CD4+ Th subsets and their contribution to inflammation through cytokine production indicate declining metabolic health, that is, insulin resistance and T2D. While some Th subset alterations are consistent between mice and humans with obesity, some changes mainly characterize male mice, whereas female mice often resist obesity and inflammation. However, protection from obesity and inflammation is not observed in human females, who can develop obesity-related T-cell inflammation akin to males. The decline in female sex hormones after menopause is also implicated in promoting obesity and inflammation. Age is a second underappreciated factor for defining and regulating obesity-associated inflammation toward translating basic science findings to the clinic. Weight loss in mice and humans, in parallel with these other factors, does not resolve obesity-associated inflammation. Instead, inflammation persists amid modest changes in CD4+ T cell frequencies, highlighting the need for further research into resolving changes in T-cell function after weight loss. How lingering inflammation after weight loss affecting the common struggle to maintain lower weight is unknown. Semaglutide, a newly popular pharmaceutical used for treating T2D and reversing obesity, holds promise for alleviating obesity-associated health complications, yet its impact on T-cell-mediated inflammation remains unexplored. Further work in this area could significantly contribute to the scientific understanding of the impacts of weight loss and sex/hormones in obesity and obesity-associated metabolic decline.
    Keywords:  Type 2 diabetes; aging; inflammation; regulatory T cells; sex differences