bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–05–05
fourteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Immunometabolism of CD8+ T cell differentiation in cancer.
  2. ER-associated degradation adapter Sel1L is required for CD8+ T cell function and memory formation following acute viral infection.
  3. Functionalized nanowires for miRNA-mediated therapeutic programming of naïve T cells.
  4. The factor inhibiting HIF regulates T cell differentiation and anti-tumour efficacy.
  5. The effect of T cell aging on the change of human tissue structure.
  6. PD1 blockade improves survival and CD8+ cytotoxic capacity, without increasing inflammation, during normal microbial experience in old mice.
  7. Cellular senescence is a double-edged sword in regulating aged immune responses to influenza.
  8. Adaptive immunity and atherosclerosis: aging at its crossroads.
  9. Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc.
  10. CD8+ T cell-based cancer immunotherapy.
  11. Cycling back to folate metabolism in cancer.
  12. Protective Anti-Chlamydial Vaccine Regimen-Induced CD4+ T cell Response Mediates Early Inhibition of Pathogenic CD8+ T cell Response Following Genital Challenge.
  13. The role of CD20+ T cells: Insights in human peripheral blood.
  14. Image-based quantification of mitochondrial iron uptake via Mitoferrin-2.
  1. Trends Cancer. 2024 Apr 30. pii: S2405-8033(24)00059-1. [Epub ahead of print]
    Immunometabolism of CD8+ T cell differentiation in cancer.
    Hao Shi, Sidi Chen, Hongbo Chi.
      CD8+ cytotoxic T lymphocytes (CTLs) are central mediators of tumor immunity and immunotherapies. Upon tumor antigen recognition, CTLs differentiate from naive/memory-like toward terminally exhausted populations with more limited function against tumors. Such differentiation is regulated by both immune signals, including T cell receptors (TCRs), co-stimulation, and cytokines, and metabolism-associated processes. These immune signals shape the metabolic landscape via signaling, transcriptional and post-transcriptional mechanisms, while metabolic processes in turn exert spatiotemporal effects to modulate the strength and duration of immune signaling. Here, we review the bidirectional regulation between immune signals and metabolic processes, including nutrient uptake and intracellular metabolic pathways, in shaping CTL differentiation and exhaustion. We also discuss the mechanisms underlying how specific nutrient sources and metabolite-mediated signaling events orchestrate CTL biology. Understanding how metabolic programs and their interplay with immune signals instruct CTL differentiation and exhaustion is crucial to uncover tumor-immune interactions and design novel immunotherapies.
    Keywords:  T cell differentiation; TCR; antitumor function; cytokines; exhaustion; mitochondrial fitness
    DOI:  https://doi.org/10.1016/j.trecan.2024.03.010
  2. Cell Rep. 2024 Apr 29. pii: S2211-1247(24)00484-4. [Epub ahead of print]43(5): 114156
    ER-associated degradation adapter Sel1L is required for CD8+ T cell function and memory formation following acute viral infection.
    Luis O Correa-Medero, Shayna E Jankowski, Hanna S Hong, Nicholas D Armas, Aditi I Vijendra, Mack B Reynolds, Garrett M Fogo, Dominik Awad, Alexander T Dils, Kantaro A Inoki, Reid G Williams, Annabelle M Ye, Nadezhda Svezhova, Francisco Gomez-Rivera, Kathleen L Collins, Mary X O'Riordan, Thomas H Sanderson, Costas A Lyssiotis, Shannon A Carty.
      The maintenance of antigen-specific CD8+ T cells underlies the efficacy of vaccines and immunotherapies. Pathways contributing to CD8+ T cell loss are not completely understood. Uncovering the pathways underlying the limited persistence of CD8+ T cells would be of significant benefit for developing novel strategies of promoting T cell persistence. Here, we demonstrate that murine CD8+ T cells experience endoplasmic reticulum (ER) stress following activation and that the ER-associated degradation (ERAD) adapter Sel1L is induced in activated CD8+ T cells. Sel1L loss limits CD8+ T cell function and memory formation following acute viral infection. Mechanistically, Sel1L is required for optimal bioenergetics and c-Myc expression. Finally, we demonstrate that human CD8+ T cells experience ER stress upon activation and that ER stress is negatively associated with improved T cell functionality in T cell-redirecting therapies. Together, these results demonstrate that ER stress and ERAD are important regulators of T cell function and persistence.
    Keywords:  CD8 T cell; CP: Immunology; ER stress; ERAD; Myc; T cell memory; immunometabolism; protein homeostasis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114156
  3. Nat Nanotechnol. 2024 Apr 29.
    Functionalized nanowires for miRNA-mediated therapeutic programming of naïve T cells.
    Kristel J Yee Mon, Sungwoong Kim, Zhonghao Dai, Jessica D West, Hongya Zhu, Ritika Jain, Andrew Grimson, Brian D Rudd, Ankur Singh.
      Cellular programming of naïve T cells can improve the efficacy of adoptive T-cell therapy. However, the current ex vivo engineering of T cells requires the pre-activation of T cells, which causes them to lose their naïve state. In this study, cationic-polymer-functionalized nanowires were used to pre-program the fate of primary naïve CD8+ T cells to achieve a therapeutic response in vivo. This was done by delivering single or multiple microRNAs to primary naïve mouse and human CD8+ T cells without pre-activation. The use of nanowires further allowed for the delivery of large, whole lentiviral particles with potential for long-term integration. The combination of deletion and overexpression of miR-29 and miR-130 impacted the ex vivo T-cell differentiation fate from the naïve state. The programming of CD8+ T cells using nanowire-delivered co-delivery of microRNAs resulted in the modulation of T-cell fitness by altering the T-cell proliferation, phenotypic and transcriptional regulation, and secretion of effector molecules. Moreover, the in vivo adoptive transfer of murine CD8+ T cells programmed through the nanowire-mediated dual delivery of microRNAs provided enhanced immune protection against different types of intracellular pathogen (influenza and Listeria monocytogenes). In vivo analyses demonstrated that the simultaneous alteration of miR-29 and miR-130 levels in naïve CD8+ T cells reduces the persistence of canonical memory T cells whereas increases the population of short-lived effector T cells. Nanowires could potentially be used to modulate CD8+ T-cell differentiation and achieve a therapeutic response in vivo without the need for pre-activation.
    DOI:  https://doi.org/10.1038/s41565-024-01649-7
  4. Front Immunol. 2024 ;15 1293723
    The factor inhibiting HIF regulates T cell differentiation and anti-tumour efficacy.
    David Bargiela, Pedro P Cunha, Pedro Veliça, Lena C M Krause, Madara Brice, Laura Barbieri, Milos Gojkovic, Iosifina P Foskolou, Helene Rundqvist, Randall S Johnson.
      T cells must adapt to variations in tissue microenvironments; these adaptations include the degree of oxygen availability. The hypoxia-inducible factor (HIF) transcription factors control much of this adaptation, and thus regulate many aspects of T cell activation and function. The HIFs are in turn regulated by oxygen-dependent hydroxylases: both the prolyl hydroxylases (PHDs) which interact with the VHL tumour suppressor and control HIF turnover, and the asparaginyl hydroxylase known as the Factor inhibiting HIF (FIH), which modulates HIF transcriptional activity. To determine the role of this latter factor in T cell function, we generated T cell-specific FIH knockout mice. We found that FIH regulates T cell fate and function in a HIF-dependent manner and show that the effects of FIH activity occur predominantly at physiological oxygen concentrations. T cell-specific loss of FIH boosts T cell cytotoxicity, augments T cell expansion in vivo, and improves anti-tumour immunotherapy in mice. Specifically inhibiting FIH in T cells may therefore represent a promising strategy for cancer immunotherapy.
    Keywords:  T cells; factor inhibiting HIF; hypoxia-inducible factor; immunotherapy; imunometabolism
    DOI:  https://doi.org/10.3389/fimmu.2024.1293723
  5. Immun Ageing. 2024 Apr 30. 21(1): 26
    The effect of T cell aging on the change of human tissue structure.
    Ling-Ling Xu, Xiang Chen, Jing-Ping Cheng.
      The trend of aging of the global population is becoming more and more significant, and the incidence of age-related diseases continues to rise.This phenomenon makes the problem of aging gradually attracted wide attention of the society, and gradually developed into an independent research field.As a vital defense mechanism of the human body, the immune system changes significantly during the aging process.Age-induced changes in the body's immune system are considered harmful and are commonly referred to as immune aging, which may represent the beginning of systemic aging.Immune cells, especially T cells, are the biggest influencers and participants in age-related deterioration of immune function, making older people more susceptible to different age-related diseases.More and more evidence shows that T cells play an important role in the change of human tissue structure after aging, which fundamentally affects the health and survival of the elderly.In this review, we discuss the general characteristics of age-related T cell immune alterations and the possible effects of aging T cells in various tissue structures in the human body.
    Keywords:  Aging; Blood vessels; Immune aging; Intestinal flora; Skeletal muscle; T cell aging
    DOI:  https://doi.org/10.1186/s12979-024-00433-4
  6. Nat Aging. 2024 Apr 30.
    PD1 blockade improves survival and CD8+ cytotoxic capacity, without increasing inflammation, during normal microbial experience in old mice.
    Korbyn J V Dahlquist, Matthew A Huggins, Matthew J Yousefzadeh, Carolina Soto-Palma, Stephanie H Cholensky, Mark Pierson, Declan M Smith, Sara E Hamilton, Christina D Camell.
      By 2030, individuals 65 years of age or older will make up approximately 20% of the world's population1. Older individuals are at the highest risk for mortality from infections, largely due to the pro-inflammatory, dysfunctional immune response, which is collectively known as immunosenescence2. During aging, CD8+ T cells acquire an exhausted phenotype, including increased expression of inhibitory receptors, such as programmed cell death 1 (PD1), a decline in effector function and elevated expression of inflammatory factors3-7. PD1 reduces T cell receptor activity via SHP2-dependent dephosphorylation of multiple pathways; accordingly, inhibiting PD1 activity through monoclonal antibodies increases CD8+ T cell effector response in young mice8-11. Attempts to improve CD8+ T cell responses by blocking inhibitory receptors are attractive; however, they can lead to adverse immune events due to overamplification of T cell receptor signaling and T cell activation12,13. Here we investigated the effect of monoclonal anti-PD1 immunotherapy during normal microbial experience, otherwise known as exposure to dirty mice, to determine whether it either improves exhausted CD8+ T cell responses in old mice or leads to a heightened inflammatory response and increased mortality.
    DOI:  https://doi.org/10.1038/s43587-024-00620-4
  7. Aging Cell. 2024 Apr 30. e14162
    Cellular senescence is a double-edged sword in regulating aged immune responses to influenza.
    Blake L Torrance, Andreia N Cadar, Hunter A Panier, Dominique E Martin, Erica C Lorenzo, Evan R Jellison, Jenna M Bartley, Laura Haynes.
      Clearance of senescent cells has demonstrated therapeutic potential in the context of chronic age-related diseases. Little is known, however, how clearing senescent cells affects the ability to respond to an acute infection and form quality immunological memory. We aimed to probe the effects of clearing senescent cells in aged mice on the immune response to influenza (flu) infection. We utilized a p16 trimodality reporter mouse model (p16-3MR) to allow for identification and selective clearance of p16-expressing cells upon administration of ganciclovir (GCV). While p16-expressing cells may exacerbate dysfunctional responses to a primary infection, our data suggest they may play a role in fostering memory cell generation. We demonstrate that although clearance of p16-expressing cells enhanced viral clearance, this also severely limited antibody production in the lungs of flu-infected aged mice. 30 days later, there were fewer flu-specific CD8 memory T cells and lower levels of flu-specific antibodies in the lungs of GCV-treated mice. Furthermore, GCV-treated mice were unable to mount an optimal memory response and demonstrated increased viral load following heterosubtypic challenge. These results suggest that targeting senescent cells may potentiate primary responses while limiting the ability to form durable and protective immune memory with age.
    Keywords:  T cells; aging; influenza; memory; p16; senescence
    DOI:  https://doi.org/10.1111/acel.14162
  8. Front Immunol. 2024 ;15 1350471
    Adaptive immunity and atherosclerosis: aging at its crossroads.
    Roy P M Snijckers, Amanda C Foks.
      Adaptive immunity plays a profound role in atherosclerosis pathogenesis by regulating antigen-specific responses, inflammatory signaling and antibody production. However, as we age, our immune system undergoes a gradual functional decline, a phenomenon termed "immunosenescence". This decline is characterized by a reduction in proliferative naïve B- and T cells, decreased B- and T cell receptor repertoire and a pro-inflammatory senescence associated secretory profile. Furthermore, aging affects germinal center responses and deteriorates secondary lymphoid organ function and structure, leading to impaired T-B cell dynamics and increased autoantibody production. In this review, we will dissect the impact of aging on adaptive immunity and the role played by age-associated B- and T cells in atherosclerosis pathogenesis, emphasizing the need for interventions that target age-related immune dysfunction to reduce cardiovascular disease risk.
    Keywords:  adaptive immunity; aging; atherosclerosis; immunosenescence; inflammaging
    DOI:  https://doi.org/10.3389/fimmu.2024.1350471
  9. Nat Metab. 2024 May 03.
    Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc.
    Juhong Wang, Yannan Yang, Fei Shao, Ying Meng, Dong Guo, Jie He, Zhimin Lu.
      Acetate, a precursor of acetyl-CoA, is instrumental in energy production, lipid synthesis and protein acetylation. However, whether acetate reprogrammes tumour metabolism and plays a role in tumour immune evasion remains unclear. Here, we show that acetate is the most abundant short-chain fatty acid in human non-small cell lung cancer tissues, with increased tumour-enriched acetate uptake. Acetate-derived acetyl-CoA induces c-Myc acetylation, which is mediated by the moonlighting function of the metabolic enzyme dihydrolipoamide S-acetyltransferase. Acetylated c-Myc increases its stability and subsequent transcription of the genes encoding programmed death-ligand 1, glycolytic enzymes, monocarboxylate transporter 1 and cell cycle accelerators. Dietary acetate supplementation promotes tumour growth and inhibits CD8+ T cell infiltration, whereas disruption of acetate uptake inhibits immune evasion, which increases the efficacy of anti-PD-1-based therapy. These findings highlight a critical role of acetate promoting tumour growth beyond its metabolic role as a carbon source by reprogramming tumour metabolism and immune evasion, and underscore the potential of controlling acetate metabolism to curb tumour growth and improve the response to immune checkpoint blockade therapy.
    DOI:  https://doi.org/10.1038/s42255-024-01037-4
  10. J Transl Med. 2024 Apr 29. 22(1): 394
    CD8+ T cell-based cancer immunotherapy.
    Yanxia Chen, Dingning Yu, Hui Qian, Yinghong Shi, Zhimin Tao.
      The immune system in humans is a defense department against both exogenous and endogenous hazards, where CD8+ T cells play a crucial role in opposing pathological threats. Various immunotherapies based on CD8+ T cells have emerged in recent decades, showing their promising results in treating intractable diseases. However, in the fight against the constantly changing and evolving cancers, the formation and function of CD8+ T cells can be challenged by tumors that might train a group of accomplices to resist the T cell killing. As cancer therapy stepped into the era of immunotherapy, understanding the physiological role of CD8+ T cells, studying the machinery of tumor immune escape, and thereby formulating different therapeutic strategies become the imperative missions for clinical and translational researchers to fulfill. After brief basics of CD8+ T cell-based biology is covered, this review delineates the mechanisms of tumor immune escape and discusses different cancer immunotherapy regimens with their own advantages and setbacks, embracing challenges and perspectives in near future.
    Keywords:  CAR-T; CD8+ T cell; Cancer therapy; Checkpoint inhibitor; Solid tumor
    DOI:  https://doi.org/10.1186/s12967-024-05134-6
  11. Nat Cancer. 2024 May 02.
    Cycling back to folate metabolism in cancer.
    Younghwan Lee, Karen H Vousden, Marc Hennequart.
      Metabolic changes contribute to cancer initiation and progression through effects on cancer cells, the tumor microenvironment and whole-body metabolism. Alterations in serine metabolism and the control of one-carbon cycles have emerged as critical for the development of many tumor types. In this Review, we focus on the mitochondrial folate cycle. We discuss recent evidence that, in addition to supporting nucleotide synthesis, mitochondrial folate metabolism also contributes to metastasis through support of antioxidant defense, mitochondrial protein synthesis and the overflow of excess formate. These observations offer potential therapeutic opportunities, including the modulation of formate metabolism through dietary interventions and the use of circulating folate cycle metabolites as biomarkers for cancer detection.
    DOI:  https://doi.org/10.1038/s43018-024-00739-8
  12. Pathog Dis. 2024 Apr 29. pii: ftae008. [Epub ahead of print]
    Protective Anti-Chlamydial Vaccine Regimen-Induced CD4+ T cell Response Mediates Early Inhibition of Pathogenic CD8+ T cell Response Following Genital Challenge.
    Ashlesh K Murthy, Erika Wright-McAfee, Katerina Warda, Lindsay N Moy, Nhi Bui, Tarakarama Musunuri, S Manam, Clemence Z Chako, Kyle H Ramsey, Weidang Li.
      We have demonstrated previously that TNF-α-producing CD8 + T cells mediate chlamydial pathogenesis, likely in an antigen (Ag)-specific fashion. Here we hypothesize that inhibition of Ag-specific CD8 + T cell response after immunization and/or challenge would correlate with protection against oviduct pathology induced by a protective vaccine regimen. Intranasal (i.n.) live chlamydial elementary body (EB), intramuscular (i.m.) live EB, or i.n. irrelevant antigen, bovine serum albumin (BSA), immunized animals induced near-total protection, 50% protection, or no protection, respectively against oviduct pathology following i.vag. C. muridarum challenge. In these models, we evaluated Ag-specific CD8 + T cell cytokine response at various time-periods after immunization or challenge. The results show protective efficacy of vaccine regimens correlated with reduction of Ag-specific CD8 + T cell TNF-α responses following i.vag. chlamydial challenge, not after immunization. Depletion of CD4 + T cells abrogated, whereas adoptive transfer of Ag-specific CD4 + T cells induced the significant reduction of Ag-specific CD8+ T cell TNF- α response after chlamydial challenge. In conclusion, protective anti-chlamydial vaccine regimens induce Ag-specific CD4 + T cell response that mediate early inhibition of pathogenic CD8 + T cell response following challenge and may serve as a predictive biomarker of protection against Chlamydia -induced chronic pathologies.
    Keywords:  CD4+ T cells; CD8+ T cells; Chlamydia; protective immunity; reproductive pathology
    DOI:  https://doi.org/10.1093/femspd/ftae008
  13. Cytometry B Clin Cytom. 2024 May 02.
    The role of CD20+ T cells: Insights in human peripheral blood.
    Aryane Cruz Oliveira Pinho, Pedro Barbosa, Maria João Pereira, Artur Paiva, Eugenia Carvalho, Paula Laranjeira.
      CD20+ T cells constitute a small subset of T cells. These are found among CD4+, CD8+, CD4+CD8+, CD4-CD8- T, and TCRγδ+ T cells, and have been poorly characterized. The aim of this study was to characterize peripheral blood (PB) CD20+ T cells and compare them to their PB CD20- T cell counterparts. PB from 17 healthy individuals was collected. The distribution of CD20+ T cells among maturation-associated T cells compartments (naïve, central memory, transitional memory, effector memory, and effector T cells), their polarization, activation status, and expression of immune-regulatory proteins were evaluated by flow cytometry. Their function was also assessed, by measuring IFN-γ, TNF-α, and IL-17 production. Compared with CD20- T cells, CD20+ T cells represent a higher proportion of transitional memory cells. Furthermore, CD20+ T cells display a proinflammatory phenotype, characterized by the expansion of Th1, Th1/17, and Tc1 cell subsets , associated to a high expression of activation (CD25) and exhaustion (PD-1) markers. In addition, the simultaneous production of the proinflammatory cytokines IFN-γ, TNF-α, and IL-17 was also detected in CD4+CD20+ T cells. Our results show that CD20+ T cells are phenotypically and functionally different from CD20- T cells, suggesting that these cells are a distinct subset of T cells.
    Keywords:  CD20+ T cells; activation and exhaustion status; cytokines; flow cytometry; functional compartments; polarization
    DOI:  https://doi.org/10.1002/cyto.b.22178
  14. Mitochondrion. 2024 Apr 29. pii: S1567-7249(24)00047-3. [Epub ahead of print] 101889
    Image-based quantification of mitochondrial iron uptake via Mitoferrin-2.
    Marcello Polesel, Mattheus H E Wildschut, Cédric Doucerain, Michael Kuhn, Anna Flace, Anna-Lena Steck, Maria Wilhelm, Alvaro Ingles-Prieto, Tabea Wiedmer, Giulio Superti-Furga, Vania Manolova, Franz Dürrenberger.
      Iron is a trace element that is critical for most living organisms and plays a key role in a wide variety of metabolic processes. In the mitochondrion, iron is involved in producing iron-sulfur clusters and synthesis of heme and kept within physiological ranges by concerted activity of multiple molecules. Mitochondrial iron uptake is mediated by the solute carrier transporters Mitoferrin-1 (SLC25A37) and Mitoferrin-2 (SLC25A28). While Mitoferrin-1 is mainly involved in erythropoiesis, the cellular function of the ubiquitously expressed Mitoferrin-2 remains less well defined. Furthermore, Mitoferrin-2 is associated with several human diseases, including cancer, cardiovascular and metabolic diseases, hence representing a potential therapeutic target. Here, we developed a robust approach to quantify mitochondrial iron uptake mediated by Mitoferrin-2 in living cells. We utilize HEK293 cells with inducible expression of Mitoferrin-2 and measure iron-induced quenching of rhodamine B[(1,10-phenanthroline-5-yl)-aminocarbonyl]benzyl ester (RPA) fluorescence and validate this assay for medium-throughput screening. This assay may allow identification and characterization of Mitoferrin-2 modulators and could enable drug discovery for this target.
    Keywords:  Iron; Medium throughput screening assay; Mitoferrin-2; RPA; Rhodamine B[(1,10-phenanthroline-5-yl)-aminocarbonyl]benzyl ester; SLC25A28
    DOI:  https://doi.org/10.1016/j.mito.2024.101889
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