bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–03–24
fiveteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Senescent T Cells in Age-Related Diseases.
  2. Expression of the monocarboxylate transporter MCT1 is required for virus-specific mouse CD8+ T cell memory development.
  3. Alterations in metabolic pathways: a bridge between aging and weaker innate immune response.
  4. Metabolic instruction of the graft-versus-leukemia immunity.
  5. Intestinal tuft cell immune privilege enables norovirus persistence.
  6. Targeting metabolism to improve CAR-T cells therapeutic efficacy.
  7. T-cell immunity against senescence: potential role and perspectives.
  8. SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis.
  9. Cytotoxic response of tumor-infiltrating lymphocytes of head and neck cancer slice cultures under mitochondrial dysfunction.
  10. MicroRNA-7 deficiency ameliorates d-galactose-induced aging in mice by regulating senescence of Kupffer cells.
  11. The power of memory T cells minus antibodies.
  12. Detection of Nanoparticle-Mediated Change in Mitochondrial Membrane Potential in T Cells Using JC-1 Dye.
  13. CD39 expression defines exhausted CD4+ T cells associated with poor survival and immune evasion in human gastric cancer.
  14. Targeting NAD+ Metabolism to Modulate Autoimmunity and Inflammation.
  15. Editorial: Women in aging and the immune system.
  1. Aging Dis. 2024 Mar 08.
    Senescent T Cells in Age-Related Diseases.
    Pei-Jie Yu, Mei Zhou, Yan Liu, Jie Du.
      Age-induced alterations in human immunity are often considered deleterious and are referred to as immunosenescence. The immune system monitors the number of senescent cells in the body, while immunosenescence may represent the initiation of systemic aging. Immune cells, particularly T cells, are the most impacted and involved in age-related immune function deterioration, making older individuals more prone to different age-related diseases. T-cell senescence can impact the effectiveness of immunotherapies that rely on the immune system's function, including vaccines and adoptive T-cell therapies. The research and practice of using senescent T cells as therapeutic targets to intervene in age-related diseases are in their nascent stages. Therefore, in this review, we summarize recent related literature to investigate the characteristics of senescent T cells as well as their formation mechanisms, relationship with various aging-related diseases, and means of intervention. The primary objective of this article is to explore the prospects and possibilities of therapeutically targeting senescent T cells, serving as a valuable resource for the development of immunotherapy and treatment of age-related diseases.
    DOI:  https://doi.org/10.14336/AD.2024.0219
  2. Proc Natl Acad Sci U S A. 2024 Mar 26. 121(13): e2306763121
    Expression of the monocarboxylate transporter MCT1 is required for virus-specific mouse CD8+ T cell memory development.
    Stefania D'Aria, Céline Maquet, Shuang Li, Suveera Dhup, Anouk Lepez, Arnaud Kohler, Vincent F Van Hée, Rajesh K Dadhich, Marine Frenière, Fabienne Andris, Ivan Nemazanyy, Pierre Sonveaux, Bénédicte Machiels, Laurent Gillet, Michel Y Braun.
      Lactate-proton symporter monocarboxylate transporter 1 (MCT1) facilitates lactic acid export from T cells. Here, we report that MCT1 is mandatory for the development of virus-specific CD8+ T cell memory. MCT1-deficient T cells were exposed to acute pneumovirus (pneumonia virus of mice, PVM) or persistent γ-herpesvirus (Murid herpesvirus 4, MuHV-4) infection. MCT1 was required for the expansion of virus-specific CD8+ T cells and the control of virus replication in the acute phase of infection. This situation prevented the subsequent development of virus-specific T cell memory, a necessary step in containing virus reactivation during γ-herpesvirus latency. Instead, persistent active infection drove virus-specific CD8+ T cells toward functional exhaustion, a phenotype typically seen in chronic viral infections. Mechanistically, MCT1 deficiency sequentially impaired lactic acid efflux from activated CD8+ T cells, caused an intracellular acidification inhibiting glycolysis, disrupted nucleotide synthesis in the upstream pentose phosphate pathway, and halted cell proliferation which, ultimately, promoted functional CD8+ T cell exhaustion instead of memory development. Taken together, our data demonstrate that MCT1 expression is mandatory for inducing T cell memory and controlling viral infection by CD8+ T cells.
    Keywords:  T cell exhaustion; T cell memory development; lactate transport; monocarboxylate transporters (MCTs); virus latency
    DOI:  https://doi.org/10.1073/pnas.2306763121
  3. Front Aging. 2024 ;5 1358330
    Alterations in metabolic pathways: a bridge between aging and weaker innate immune response.
    Zahra Saleh, Sara Mirzazadeh, Fatemeh Mirzaei, Kamran Heidarnejad, Seppo Meri, Kurosh Kalantar.
      Aging is a time-dependent progressive physiological process, which results in impaired immune system function. Age-related changes in immune function increase the susceptibility to many diseases such as infections, autoimmune diseases, and cancer. Different metabolic pathways including glycolysis, tricarboxylic acid cycle, amino acid metabolism, pentose phosphate pathway, fatty acid oxidation and fatty acid synthesis regulate the development, differentiation, and response of adaptive and innate immune cells. During aging all these pathways change in the immune cells. In addition to the changes in metabolic pathways, the function and structure of mitochondria also have changed in the immune cells. Thereby, we will review changes in the metabolism of different innate immune cells during the aging process.
    Keywords:  age-related diseases; aging; immunometabolism; innate immunity; metabolic pathways
    DOI:  https://doi.org/10.3389/fragi.2024.1358330
  4. Front Immunol. 2024 ;15 1347492
    Metabolic instruction of the graft-versus-leukemia immunity.
    Ann-Cathrin Burk, Petya Apostolova.
      Allogeneic hematopoietic cell transplantation (allo-HCT) is frequently performed to cure hematological malignancies, such as acute myeloid leukemia (AML), through the graft-versus-leukemia (GVL) effect. In this immunological process, donor immune cells eliminate residual cancer cells in the patient and exert tumor control through immunosurveillance. However, GVL failure and subsequent leukemia relapse are frequent and associated with a dismal prognosis. A better understanding of the mechanisms underlying AML immune evasion is essential for developing novel therapeutic strategies to boost the GVL effect. Cellular metabolism has emerged as an essential regulator of survival and cell fate for both cancer and immune cells. Leukemia and T cells utilize specific metabolic programs, including the orchestrated use of glucose, amino acids, and fatty acids, to support their growth and function. Besides regulating cell-intrinsic processes, metabolism shapes the extracellular environment and plays an important role in cell-cell communication. This review focuses on recent advances in the understanding of how metabolism might affect the anti-leukemia immune response. First, we provide a general overview of the mechanisms of immune escape after allo-HCT and an introduction to leukemia and T cell metabolism. Further, we discuss how leukemia and myeloid cell metabolism contribute to an altered microenvironment that impairs T cell function. Next, we review the literature linking metabolic processes in AML cells with their inhibitory checkpoint ligand expression. Finally, we focus on recent findings concerning the role of systemic metabolism in sustained GVL efficacy. While the majority of evidence in the field still stems from basic and preclinical studies, we discuss translational findings and propose further avenues for bridging the gap between bench and bedside.
    Keywords:  T cells; acute myeloid leukemia; allogeneic hematopoietic cell transplantation; anti-tumor immunity; graft-versus-leukemia effect; metabolism
    DOI:  https://doi.org/10.3389/fimmu.2024.1347492
  5. Sci Immunol. 2024 Mar 22. 9(93): eadi7038
    Intestinal tuft cell immune privilege enables norovirus persistence.
    Madison S Strine, Eric Fagerberg, Patrick W Darcy, Gabriel M Barrón, Renata B Filler, Mia Madel Alfajaro, Nicole D'Angelo-Gavrish, Fang Wang, Vincent R Graziano, Bridget L Menasché, Martina Damo, Ya-Ting Wang, Michael R Howitt, Sanghyun Lee, Nikhil S Joshi, Daniel Mucida, Craig B Wilen.
      The persistent murine norovirus strain MNVCR6 is a model for human norovirus and enteric viral persistence. MNVCR6 causes chronic infection by directly infecting intestinal tuft cells, rare chemosensory epithelial cells. Although MNVCR6 induces functional MNV-specific CD8+ T cells, these lymphocytes fail to clear infection. To examine how tuft cells promote immune escape, we interrogated tuft cell interactions with CD8+ T cells by adoptively transferring JEDI (just EGFP death inducing) CD8+ T cells into Gfi1b-GFP tuft cell reporter mice. Unexpectedly, some intestinal tuft cells partially resisted JEDI CD8+ T cell-mediated killing-unlike Lgr5+ intestinal stem cells and extraintestinal tuft cells-despite seemingly normal antigen presentation. When targeting intestinal tuft cells, JEDI CD8+ T cells predominantly adopted a T resident memory phenotype with decreased effector and cytotoxic capacity, enabling tuft cell survival. JEDI CD8+ T cells neither cleared nor prevented MNVCR6 infection in the colon, the site of viral persistence, despite targeting a virus-independent antigen. Ultimately, we show that intestinal tuft cells are relatively resistant to CD8+ T cells independent of norovirus infection, representing an immune-privileged niche that can be leveraged by enteric microbes.
    DOI:  https://doi.org/10.1126/sciimmunol.adi7038
  6. Chin Med J (Engl). 2024 Mar 19.
    Targeting metabolism to improve CAR-T cells therapeutic efficacy.
    Shasha Liu, Yuyu Zhao, Yaoxin Gao, Feng Li, Yi Zhang.
       ABSTRACT: Chimeric antigen receptor T (CAR-T) cell therapy achieved advanced progress in the treatment of hematological tumors. However, the application of CAR-T cell therapy for solid tumors still faces many challenges. Competition with tumor cells for metabolic resources in an already nutrient-poor tumor microenvironment is a major contributing cause to CAR-T cell therapy's low effectiveness. Abnormal metabolic processes are now acknowledged to shape the tumor microenvironment, which is characterized by increased interstitial fluid pressure, low pH level, hypoxia, accumulation of immunosuppressive metabolites, and mitochondrial dysfunction. These factors are important contributors to restriction of T cell proliferation, cytokine release, and suppression of tumor cell-killing ability. This review provides an overview of how different metabolites regulate T cell activity, analyzes the current dilemmas, and proposes key strategies to reestablish the CAR-T cell therapy's effectiveness through targeting metabolism, with the aim of providing new strategies to surmount the obstacle in the way of solid tumor CAR-T cell treatment.
    DOI:  https://doi.org/10.1097/CM9.0000000000003046
  7. Front Immunol. 2024 ;15 1360109
    T-cell immunity against senescence: potential role and perspectives.
    Kseniia Matveeva, Mariia Vasilieva, Ekaterina Minskaia, Stanislav Rybtsov, Daniil Shevyrev.
      The development of age-associated diseases is related to the accumulation of senescent cells in the body. These are old non-functional cells with impaired metabolism, which are unable to divide. Such cells are also resistant to programmed cell death and prone to spontaneous production of some inflammatory factors. The accumulation of senescent cells is related to the age-associated dysfunction of organs and tissues as well as chronic inflammation that enhances with age. In the young organism, senescent cells are removed with the innate immunity system. However, the efficiency of this process decreases with age. Nowadays, more and more evidences are accumulating to support the involvement of specific immunity and T-lymphocytes in the fight against senescent cells. It has great physiological importance since the efficient elimination of senescent cells requires a high diversity of antigen-recognizing receptors to cover the entire spectrum of senescent-associated antigens with high precision and specificity. Developing the approaches of T-cell immunity stimulation to generate or amplify a physiological immune response against senescent cells can provide new perspectives to extend active longevity. In this mini-review, the authors summarize the current understanding of the role of T-cell immunity in the fight against senescent cells and discuss the prospects of stimulating adaptive immunity for combating the accumulation of senescent cells that occurs with age.
    Keywords:  SASP (senescence-associated secretory phenotype); T-cells (or lymphocytes); adaptive immunity; immunoaging; retroelement; senescence; senolytic agent; transposable element (TE)
    DOI:  https://doi.org/10.3389/fimmu.2024.1360109
  8. Cell Rep. 2024 Mar 19. pii: S2211-1247(24)00303-6. [Epub ahead of print]43(4): 113975
    SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis.
    Sarah A Tucker, Song-Hua Hu, Sejal Vyas, Albert Park, Shakchhi Joshi, Aslihan Inal, Tiffany Lam, Emily Tan, Kevin M Haigis, Marcia C Haigis.
      The intestine is a highly metabolic tissue, but the metabolic programs that influence intestinal crypt proliferation, differentiation, and regeneration are still emerging. Here, we investigate how mitochondrial sirtuin 4 (SIRT4) affects intestinal homeostasis. Intestinal SIRT4 loss promotes cell proliferation in the intestine following ionizing radiation (IR). SIRT4 functions as a tumor suppressor in a mouse model of intestinal cancer, and SIRT4 loss drives dysregulated glutamine and nucleotide metabolism in intestinal adenomas. Intestinal organoids lacking SIRT4 display increased proliferation after IR stress, along with increased glutamine uptake and a shift toward de novo nucleotide biosynthesis over salvage pathways. Inhibition of de novo nucleotide biosynthesis diminishes the growth advantage of SIRT4-deficient organoids after IR stress. This work establishes SIRT4 as a modulator of intestinal metabolism and homeostasis in the setting of DNA-damaging stress.
    Keywords:  CP: Cancer; SIRT4; glutamine; intestinal organoids; irradiation; nucleotide biosynthesis; nucleotide metabolism; sirtuin
    DOI:  https://doi.org/10.1016/j.celrep.2024.113975
  9. Front Oncol. 2024 ;14 1364577
    Cytotoxic response of tumor-infiltrating lymphocytes of head and neck cancer slice cultures under mitochondrial dysfunction.
    Maria do Carmo Greier, Annette Runge, Jozsef Dudas, Roland Hartl, Matthias Santer, Daniel Dejaco, Teresa Bernadette Steinbichler, Julia Federspiel, Christof Seifarth, Marko Konschake, Susanne Sprung, Sieghart Sopper, Avneet Randhawa, Melissa Mayr, Benedikt Gabriel Hofauer, Herbert Riechelmann.
       Background: Head and neck squamous cell carcinomas (HNSCC) are highly heterogeneous tumors. In the harsh tumor microenvironment (TME), metabolic reprogramming and mitochondrial dysfunction may lead to immunosuppressive phenotypes. Aerobic glycolysis is needed for the activation of cytotoxic T-cells and the absence of glucose may hamper the full effector functions of cytotoxic T-cells. To test the effect of mitochondrial dysfunction on cytotoxic T cell function, slice cultures (SC) of HNSCC cancer were cultivated under different metabolic conditions.
    Methods: Tumor samples from 21 patients with HNSCC were collected, from which, SC were established and cultivated under six different conditions. These conditions included high glucose, T cell stimulation, and temporarily induced mitochondrial dysfunction (MitoDys) using FCCP and oligomycin A with or without additional T cell stimulation, high glucose and finally, a control medium. Over three days of cultivation, sequential T cell stimulation and MitoDys treatments were performed. Supernatant was collected, and SC were fixed and embedded. Granzyme B was measured in the supernatant and in the SC via immunohistochemistry (IHC). Staining of PD1, CD8/Ki67, and cleaved-caspase-3 (CC3) were performed in SC.
    Results: Hematoxylin eosin stains showed that overall SC quality remained stable over 3 days of cultivation. T cell stimulation, both alone and combined with MitoDys, led to significantly increased granzyme levels in SC and in supernatant. Apoptosis following T cell stimulation was observed in tumor and stroma. Mitochondrial dysfunction alone increased apoptosis in tumor cell aggregates. High glucose concentration alone had no impact on T cell activity and apoptosis. Apoptosis rates were significantly lower under conditions with high glucose and MitoDys (p=0.03).
    Conclusion: Stimulation of tumor-infiltrating lymphocytes in SC was feasible, which led to increased apoptosis in tumor cells. Induced mitochondrial dysfunction did not play a significant role in the activation and function of TILs in SC of HNSCC. Moreover, high glucose concentration did not promote cytotoxic T cell activity in HNSCC SC.
    Keywords:  cytotoxic T-cells; head and neck carcinoma; immune response; mitochondrial dysfunction; mitochondrial electron transport chain
    DOI:  https://doi.org/10.3389/fonc.2024.1364577
  10. Aging Cell. 2024 Mar 17. e14145
    MicroRNA-7 deficiency ameliorates d-galactose-induced aging in mice by regulating senescence of Kupffer cells.
    Ya Wang, Hui Qiu, Shipeng Chen, Dongmei Li, Xu Zhao, Mengmeng Guo, Nana Li, Chao Chen, Ming Qin, Ya Zhou, Daimin Xiao, Juanjuan Zhao, Lin Xu.
      Aging is intricately linked to immune system dysfunction. Recent studies have highlighted the biological function of microRNA-7 (miR-7) as a novel regulator of immune cell function and related diseases. However, the potential role of miR-7 in aging remains unexplored. Here, we investigated the contribution of miR-7 to d-gal-induced aging in mice, focusing on its regulation of senescent Kupffer cells. Our findings revealed that miR-7 deficiency significantly ameliorated the aging process, characterized by enhanced CD4+ T-cell activation. However, the adoptive transfer of miR-7-deficient CD4+ T cells failed to improve the age-related phenotype. Further analysis showed that miR-7 deficiency significantly reduced IL-1β production in liver tissue, and inhibiting IL-1β in vivo slowed down the aging process in mice. Notably, IL-1β is mainly produced by senescent Kupffer cells in the liver tissue of aging mice, and miR-7 expression was significantly up-regulated in these cells. Mechanistically, KLF4, a target of miR-7, was down-regulated in senescent Kupffer cells in aging mouse model. Furthermore, miR-7 deficiency also modulated the NF-κB activation and IL-1β production in senescent Kupffer cells through KLF4. In conclusion, our findings unveil the role of miR-7 in d-gal-induced aging in mice, highlighting its regulation of KLF4/NF-κB/IL-1β pathways in senescent Kupffer cells. This research may enhance our understanding of miRNA-based aging immune cells and offer new avenues for new intervention strategies in aging process.
    Keywords:  IL-1β; KLF4; aging; microRNA-7; senescent Kupffer cells
    DOI:  https://doi.org/10.1111/acel.14145
  11. Nat Immunol. 2024 Mar 15.
    The power of memory T cells minus antibodies.
    Thi H O Nguyen, Katherine Kedzierska.
      
    DOI:  https://doi.org/10.1038/s41590-024-01796-y
  12. Methods Mol Biol. 2024 ;2789 153-159
    Detection of Nanoparticle-Mediated Change in Mitochondrial Membrane Potential in T Cells Using JC-1 Dye.
    Ankit Shah, Marina A Dobrovolskaia.
      Alterations in mitochondrial membrane potential are associated with the generation of reactive oxygen species and cell death. While eliminating cancer cells is beneficial for cancer therapy, cytotoxicity to healthy cells may limit the therapeutic applications of mitochondria-damaging nanoparticles. Due to the critical role mitochondria play in cell viability and function, it is important to detect such alterations when studying nanomaterials for therapeutic applications. The protocol described herein utilizes JC-1 dye to detect nanoparticle-mediated changes in mitochondrial membrane potential and is intended to support mechanistic immunotoxicology studies.
    Keywords:  Membrane potential; Mitochondria; Nanoparticles; Oxidative stress; T cells
    DOI:  https://doi.org/10.1007/978-1-0716-3786-9_16
  13. Clin Transl Immunology. 2024 ;13(3): e1499
    CD39 expression defines exhausted CD4+ T cells associated with poor survival and immune evasion in human gastric cancer.
    Zhen-Quan Duan, Yu-Xian Li, Yuan Qiu, Yang Shen, Ying Wang, Yuan-Yuan Zhang, Bao-Hang Zhu, Xiao-Hong Yu, Xue-Ling Tan, Weisan Chen, Yuan Zhuang, Ping Cheng, Wei-Jun Zhang, Quan-Ming Zou, Dai-Yuan Ma, Liu-Sheng Peng.
       Objectives: CD4+ T cell helper and regulatory function in human cancers has been well characterised. However, the definition of tumor-infiltrating CD4+ T cell exhaustion and how it contributes to the immune response and disease progression in human gastric cancer (GC) remain largely unknown.
    Methods: A total of 128 GC patients were enrolled in the study. The expression of CD39 and PD-1 on CD4+ T cells in the different samples was analysed by flow cytometry. GC-infiltrating CD4+ T cell subpopulations based on CD39 expression were phenotypically and functionally assessed. The role of CD39 in the immune response of GC-infiltrating T cells was investigated by inhibiting CD39 enzymatic activity.
    Results: In comparison with CD4+ T cells from the non-tumor tissues, significantly more GC-infiltrating CD4+ T cells expressed CD39. Most GC-infiltrating CD39+CD4+ T cells exhibited CD45RA-CCR7- effector-memory phenotype expressing more exhaustion-associated inhibitory molecules and transcription factors and produced less TNF-α, IFN-γ and cytolytic molecules than their CD39-CD4+ counterparts. Moreover, ex vivo inhibition of CD39 enzymatic activity enhanced their functional potential reflected by TNF-α and IFN-γ production. Finally, increased percentages of GC-infiltrating CD39+CD4+ T cells were positively associated with disease progression and patients' poorer overall survival.
    Conclusion: Our study demonstrates that CD39 expression defines GC-infiltrating CD4+ T cell exhaustion and their immunosuppressive function. Targeting CD39 may be a promising therapeutic strategy for treating GC patients.
    Keywords:  CD39; CD4+ T cells; exhaustion; gastric cancer; immunotherapy
    DOI:  https://doi.org/10.1002/cti2.1499
  14. J Immunol. 2024 Apr 01. 212(7): 1043-1050
    Targeting NAD+ Metabolism to Modulate Autoimmunity and Inflammation.
    Jing Wu, Kim Han, Michael N Sack.
      NAD+ biology is involved in controlling redox balance, functioning as a coenzyme in numerous enzymatic reactions, and is a cofactor for Sirtuin enzymes and a substrate for multiple regulatory enzyme reactions within and outside the cell. At the same time, NAD+ levels are diminished with aging and are consumed during the development of inflammatory and autoimmune diseases linked to aberrant immune activation. Direct NAD+ augmentation via the NAD+ salvage and Priess-Handler pathways is being investigated as a putative therapeutic intervention to improve the healthspan in inflammation-linked diseases. In this review, we survey NAD+ biology and its pivotal roles in the regulation of immunity and inflammation. Furthermore, we discuss emerging studies evaluate NAD+ boosting in murine models and in human diseases, and we highlight areas of research that remain unresolved in understanding the mechanisms of action of these nutritional supplementation strategies.
    DOI:  https://doi.org/10.4049/jimmunol.2300693
  15. Front Aging. 2024 ;5 1386626
    Editorial: Women in aging and the immune system.
    Jenna M Bartley, Anshu Agrawal.
      
    Keywords:  aging; immune dysfunction; inflammaging; metformin; senolytic
    DOI:  https://doi.org/10.3389/fragi.2024.1386626
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