bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023‒04‒09
fourteen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research
  1. Artesunate targets cellular metabolism to regulate the Th17/Treg cell balance.
  2. Transcriptional programing of T cell metabolism by STAT family transcription factors.
  3. Migration of stem-like CD8 T cells between tissue microenvironments underpins successful anti-tumour immune responses.
  4. A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma.
  5. The impact of microbiome dysbiosis on T cell function within the tumor microenvironment (TME).
  6. Gut T cells help mediate fracture healing.
  7. Accessory cells precondition naïve T cells and regulatory T cells for cytokine-mediated proliferation.
  8. m6A methyltransferase METTL3 programs CD4+ T-cell activation and effector T-cell differentiation in systemic lupus erythematosus.
  9. Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA.
  10. Sucralose: not sweet enough for T cells.
  11. Distinct transcriptomic and epigenomic modalities underpin human memory T cell subsets and their activation potential.
  12. Transient inhibition of mitochondrial function by chrysin and apigenin prolong longevity via mitohormesis in C. elegans.
  13. Mitochondria in Health, Disease, and Ageing.
  14. Mediterranean diet and mitochondria: New findings.
  1. Inflamm Res. 2023 Apr 06.
    Artesunate targets cellular metabolism to regulate the Th17/Treg cell balance.
    Kun Chen, Liying Tang, Xiaolin Nong.
      INTRODUCTION: Metabolic reprogramming is one of the important mechanisms of cell differentiation, and different cells have different preferences for energy sources. During the differentiation of naive CD4 + T cells into Th17 and Treg cells, these cells show specific energy metabolism characteristics. Th17 cells depend on enhanced glycolysis, fatty acid synthesis, and glutaminolysis. In contrast, Treg cells are dependent on oxidative phosphorylation, fatty acid oxidation, and amino acid depletion. As a potent antimalarial drug, artesunate has been shown to modulate the Th17/Treg imbalance and regulate cell metabolism.METHODOLOGY: Relevant literatures on ART, cellular metabolism, glycolysis, lipid metabolism, amino acid metabolism, CD4 + T cells, Th17 cells, and Treg cells published from January 1, 2010 to now were searched in PubMed database.
    CONCLUSION: In this review, we will highlight recent advances in which artesunate can restore the Th17/Treg imbalance in disease states by altering T-cell metabolism to influence differentiation and lineage selection. Data from the current study show that few studies have focused on the effect of ART on cellular metabolism. ART can affect the metabolic characteristics of T cells (glycolysis, lipid metabolism, and amino acid metabolism) and interfere with their differentiation lineage, thereby regulating the balance of Th17/Treg and alleviating the symptoms of the disease.
    Keywords:  Amino acid metabolism; Artesunate; Cellular metabolism; Glycolysis; Lipid metabolism; Th17/Treg
    DOI:  https://doi.org/10.1007/s00011-023-01729-9
  2. Eur J Immunol. 2023 Apr 03. e2048825
    Transcriptional programing of T cell metabolism by STAT family transcription factors.
    Alejandro V Villarino.
      T cells adapt their metabolism to meet the energetic and biosynthetic demands imposed by changes in location, behavior and/or differentiation state. Many of these adaptations are controlled by cytokines. Traditionally, research on the metabolic properties of cytokines has focused on downstream signaling via the PI3K-AKT, mTOR, or ERK-MAPK pathways but recent studies indicate that JAK-STAT is also crucial. This review synthesizes current thinking on how JAK-STAT signaling influences T cell metabolism, focusing on adaptations necessary for the naïve, effector, regulatory, memory and resident-memory states. The overarching theme is that JAK-STAT has both direct and indirect effects. Direct regulation involves STATs localizing to and instructing expression of metabolism-related genes. Indirect regulation involves STATs instructing genes encoding upstream or regulatory factors, including cytokine receptors and other transcription factors, as well as non-canonical JAK-STAT activities. Cytokines impact a vast range of metabolic processes. Here, we focus on those that are most prominent in T cells; lipid, amino acid and nucleotide synthesis for anabolic metabolism, glycolysis, glutaminolysis, oxidative phosphorylation and fatty acid oxidation for catabolic metabolism. Ultimately, we advocate the idea that JAK-STAT is a key node in the complex network of signaling inputs and outputs which ensure that T cell metabolism meets lifestyle demands. This article is protected by copyright. All rights reserved.
    Keywords:  Cytokine; JAK-STAT; Metabolism; T cell
    DOI:  https://doi.org/10.1002/eji.202048825
  3. Discov Immunol. 2023 ;2(1): kyad004
    Migration of stem-like CD8 T cells between tissue microenvironments underpins successful anti-tumour immune responses.
    Bethany C Kennedy, Isaac Dean, David R Withers.
      The clinical success of immune checkpoint blockade in some patients has transformed treatment approaches in cancer and offers the hope of durable curative responses. Building from studies of chronic infection, the composition of tumour infiltrating lymphocytes and in particular, the spectrum of exhausted CD8 T cells has now been characterized in detail, profiling the phenotype, function, transcriptional regulation and even the epigenetic changes. However, what remains less clear is how intratumoural immune cells interface with populations in the periphery, both in terms of sustaining the response in cancer, but also in establishing systemic memory responses that can provide long-term protection. Here we will succinctly review the current understanding of the anti-tumour response, consider the tissue microenvironments that support key cellular subsets and the extent to which cellular migration between these sites impacts the response.
    Keywords:  CD8 T cells; cancer; immune checkpoint blockade; stem-like; trafficking
    DOI:  https://doi.org/10.1093/discim/kyad004
  4. Front Immunol. 2023 ;14 1095195
    A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma.
    Renate Pichler, Peter J Siska, Piotr Tymoszuk, Agnieszka Martowicz, Gerold Untergasser, Roman Mayr, Florian Weber, Andreas Seeber, Florian Kocher, Dominik A Barth, Martin Pichler, Martin Thurnher.
      Renal cell carcinoma (RCC) is frequently infiltrated by immune cells, a process which is governed by chemokines. CD8+ T cells in the RCC tumor microenvironment (TME) may be exhausted which most likely influence therapy response and survival. The aim of this study was to evaluate chemokine-driven T cell recruitment, T cell exhaustion in the RCC TME, as well as metabolic processes leading to their functional anergy in RCC. Eight publicly available bulk RCC transcriptome collectives (n=1819) and a single cell RNAseq dataset (n=12) were analyzed. Immunodeconvolution, semi-supervised clustering, gene set variation analysis and Monte Carlo-based modeling of metabolic reaction activity were employed. Among 28 chemokine genes available, CXCL9/10/11/CXCR3, CXCL13/CXCR5 and XCL1/XCR1 mRNA expression were significantly increased in RCC compared to normal kidney tissue and also strongly associated with tumor-infiltrating effector memory and central memory CD8+ T cells in all investigated collectives. M1 TAMs, T cells, NK cells as well as tumor cells were identified as the major sources of these chemokines, whereas T cells, B cells and dendritic cells were found to predominantly express the cognate receptors. The cluster of RCCs characterized by high chemokine expression and high CD8+ T cell infiltration displayed a strong activation of IFN/JAK/STAT signaling with elevated expression of multiple T cell exhaustion-associated transcripts. Chemokinehigh RCCs were characterized by metabolic reprogramming, in particular by downregulated OXPHOS and increased IDO1-mediated tryptophan degradation. None of the investigated chemokine genes was significantly associated with survival or response to immunotherapy. We propose a chemokine network that mediates CD8+ T cell recruitment and identify T cell exhaustion, altered energy metabolism and high IDO1 activity as key mechanisms of their suppression. Concomitant targeting of exhaustion pathways and metabolism may pose an effective approach to RCC therapy.
    Keywords:  IDO, biomarker; OXPHOS; RCC; T cells; chemokines; immunotherapy; metabolism
    DOI:  https://doi.org/10.3389/fimmu.2023.1095195
  5. Front Cell Dev Biol. 2023 ;11 1141215
    The impact of microbiome dysbiosis on T cell function within the tumor microenvironment (TME).
    Michelle P DiPalma, Joseph N Blattman.
      Insights into the effect of the microbiome's composition on immune cell function have recently been discerned and further characterized. Microbiome dysbiosis can result in functional alterations across immune cells, including those required for innate and adaptive immune responses to malignancies and immunotherapy treatment. Dysbiosis can yield changes in or elimination of metabolite secretions, such as short-chain fatty acids (SCFAs), from certain bacterial species that are believed to impact proper immune cell function. Such alterations within the tumor microenvironment (TME) can significantly affect T cell function and survival necessary for eliminating cancerous cells. Understanding these effects is essential to improve the immune system's ability to fight malignancies and the subsequent efficacy of immunotherapies that rely on T cells. In this review, we assess typical T cell response to malignancies, classify the known impact of the microbiome and particular metabolites on T cells, discuss how dysbiosis can affect their function in the TME then further describe the impact of the microbiome on T cell-based immunotherapy treatment, with an emphasis on recent developments in the field. Understanding the impact of dysbiosis on T cell function within the TME can carry substantial implications for the design of immunotherapy treatments and further our understanding of factors that could impact how the immune system combats malignancies.
    Keywords:  T cell; T cell signaling; dysbiosis; immunotherapy; metabolites; microbiome; short chain fatty acids (SCFAs); tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fcell.2023.1141215
  6. Nat Rev Rheumatol. 2023 Apr 05.
    Gut T cells help mediate fracture healing.
    Jessica McHugh.
      
    DOI:  https://doi.org/10.1038/s41584-023-00961-1
  7. Proc Natl Acad Sci U S A. 2023 Apr 11. 120(15): e2217562120
    Accessory cells precondition naïve T cells and regulatory T cells for cytokine-mediated proliferation.
    Noriko Sato, Richard N Bamford, Bonita R Bryant, Yutaka Tagaya, Thomas A Waldmann.
      Naïve T cells and regulatory T cells, when purified, do not proliferate to the γc-cytokines IL-2, IL-7, or IL-15, despite their expression of cognate cytokine receptors. Dendritic cells (DCs) enabled the T cell proliferation to these cytokines, through cell-to-cell contact, but independent of T cell receptor stimulation. This effect lasted after separation of T cells from DCs, enabling enhanced proliferation of the T cells in DC-depleted hosts. We propose calling this a "preconditioning effect". Interestingly, IL-2 alone was sufficient to induce phosphorylation and nuclear translocation of STAT5 in T cells, but could not activate MAPK and AKT pathways and failed to induce transcription of IL-2 target genes. "Preconditioning" was necessary to activate these two pathways and induced weak Ca2+ mobilization independent of calcium release-activated channels. When preconditioning was combined with IL-2, full activation of downstream mTOR, 4E-BP1 hyperphosphorylation, and prolonged S6 phosphorylation occurred. Collectively, accessory cells provide T cell preconditioning, a unique activation mechanism, controlling cytokine-mediated proliferation of T cells.
    Keywords:  dendritic cells; gamma chain cytokine; naïve T cells; proliferation; regulatory T cells
    DOI:  https://doi.org/10.1073/pnas.2217562120
  8. Mol Med. 2023 Apr 03. 29(1): 46
    m6A methyltransferase METTL3 programs CD4+ T-cell activation and effector T-cell differentiation in systemic lupus erythematosus.
    Shuang Lu, Xingyu Wei, Huan Zhu, Zhi Hu, Meiling Zheng, Jiali Wu, Cheng Zhao, Shuang Yang, Delong Feng, Sujie Jia, Hongjun Zhao, Ming Zhao.
      BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disorder in which excessive CD4+ T-cell activation and imbalanced effector T-cell differentiation play critical roles. Recent studies have implied a potential association between posttranscriptional N6-methyladenosine (m6A) modification and CD4+ T-cell-mediated humoral immunity. However, how this biological process contributes to lupus is not well understood. In this work, we investigated the role of the m6A methyltransferase like 3 (METTL3) in CD4+ T-cell activation, differentiation, and SLE pathogenesis both in vitro and in vivo.METHODS: The expression of METTL3 was knocked down and METTL3 enzyme activity was inhibited using siRNA and catalytic inhibitor, respectively. In vivo evaluation of METTL3 inhibition on CD4+ T-cell activation, effector T-cell differentiation, and SLE pathogenesis was achieved using a sheep red blood cell (SRBC)-immunized mouse model and a chronic graft versus host disease (cGVHD) mouse model. RNA-seq was performed to identify pathways and gene signatures targeted by METTL3. m6A RNA-immunoprecipitation qPCR was applied to confirm the m6A modification of METTL3 targets.
    RESULTS: METTL3 was defective in the CD4+ T cells of SLE patients. METTL3 expression varied following CD4+ T-cell activation and effector T-cell differentiation in vitro. Pharmacological inhibition of METTL3 promoted the activation of CD4+ T cells and influenced the differentiation of effector T cells, predominantly Treg cells, in vivo. Moreover, METTL3 inhibition increased antibody production and aggravated the lupus-like phenotype in cGVHD mice. Further investigation revealed that catalytic inhibition of METTL3 reduced Foxp3 expression by enhancing Foxp3 mRNA decay in a m6A-dependent manner, hence suppressing Treg cell differentiation.
    CONCLUSION: In summary, our findings demonstrated that METTL3 was required for stabilizing Foxp3 mRNA via m6A modification to maintain the Treg differentiation program. METTL3 inhibition contributed to the pathogenesis of SLE by participating in the activation of CD4+ T cells and imbalance of effector T-cell differentiation, which could serve as a potential target for therapeutic intervention in SLE.
    Keywords:  Autoimmune disorders; METTL3; N6-Methyladenosine; SLE; mRNA methylation
    DOI:  https://doi.org/10.1186/s10020-023-00643-4
  9. Free Radic Biol Med. 2023 Apr 01. pii: S0891-5849(23)00368-4. [Epub ahead of print]
    Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA.
    Mansoor Hussain, Xixia Chu, Burcin Duan Sahbaz, Samuel Gray, Komal Pekhale, Jae-Hyeon Park, Deborah L Croteau, Vilhelm A Bohr.
      Aging is accompanied by a decline in DNA repair efficiency, which leads to the accumulation of different types of DNA damage. Age-associated chronic inflammation and generation of reactive oxygen species exacerbate the aging process and age-related chronic disorders. These inflammatory processes establish conditions that favor accumulation of DNA base damage, especially 8-oxo-7,8 di-hydroguanine (8-oxoG), which in turn contributes to various age associated diseases. 8-oxoG is repaired by 8-oxoG glycosylase1 (OGG1) through the base excision repair (BER) pathway. OGG1 is present in both the cell nucleus and in mitochondria. Mitochondrial OGG1 has been implicated in mitochondrial DNA repair and increased mitochondrial function. Using transgenic mouse models and cell lines that have been engineered to have enhanced expression of mitochondria-targeted OGG1 (mtOGG1), we show that elevated levels of mtOGG1 in mitochondria can reverse aging-associated inflammation and improve functions. Old male mtOGG1Tg mice show decreased inflammation response, decreased TNFα levels and multiple pro-inflammatory cytokines. Moreover, we observe that male mtOGG1Tg mice show resistance to STING activation. Interestingly, female mtOGG1Tg mice did not respond to mtOGG1 overexpression. Further, HMC3 cells expressing mtOGG1 display decreased release of mtDNA into the cytoplasm after lipopolysacchride induction and regulate inflammation through the pSTING pathway. Also, increased mtOGG1 expression reduced LPS-induced loss of mitochondrial functions. These results suggest that mtOGG1 regulates age-associated inflammation by controlling release of mtDNA into the cytoplasm.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.03.262
  10. Nat Rev Immunol. 2023 Apr 03.
    Sucralose: not sweet enough for T cells.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-023-00873-x
  11. Commun Biol. 2023 04 03. 6(1): 363
    Distinct transcriptomic and epigenomic modalities underpin human memory T cell subsets and their activation potential.
    James R Rose, Bagdeser Akdogan-Ozdilek, Andrew R Rahmberg, Michael D Powell, Sakeenah L Hicks, Christopher D Scharer, Jeremy M Boss.
      Human memory T cells (MTC) are poised to rapidly respond to antigen re-exposure. Here, we derived the transcriptional and epigenetic programs of resting and ex vivo activated, circulating CD4+ and CD8+ MTC subsets. A progressive gradient of gene expression from naïve to TCM to TEM is observed, which is accompanied by corresponding changes in chromatin accessibility. Transcriptional changes suggest adaptations of metabolism that are reflected in altered metabolic capacity. Other differences involve regulatory modalities comprised of discrete accessible chromatin patterns, transcription factor binding motif enrichment, and evidence of epigenetic priming. Basic-helix-loop-helix factor motifs for AHR and HIF1A distinguish subsets and predict transcription networks to sense environmental changes. Following stimulation, primed accessible chromatin correlate with an augmentation of MTC gene expression as well as effector transcription factor gene expression. These results identify coordinated epigenetic remodeling, metabolic, and transcriptional changes that enable MTC subsets to ultimately respond to antigen re-encounters more efficiently.
    DOI:  https://doi.org/10.1038/s42003-023-04747-9
  12. Free Radic Biol Med. 2023 Apr 04. pii: S0891-5849(23)00370-2. [Epub ahead of print]
    Transient inhibition of mitochondrial function by chrysin and apigenin prolong longevity via mitohormesis in C. elegans.
    Yu Cheng, Bing-Hao Hou, Gui-Lin Xie, Ya-Ting Shao, Jie Yang, Chen Xu.
      Mild inhibition of mitochondrial function leads to longevity. Genetic disruption of mitochondrial respiratory components either by mutation or RNAi greatly extends the lifespan in yeast, worms, and drosophila. This has given rise to the idea that pharmacologically inhibiting mitochondrial function would be a workable strategy for postponing aging. Toward this end, we used a transgenic worm strain that expresses the firefly luciferase enzyme widely to evaluate compounds by tracking real-time ATP levels. We identified chrysin and apigenin, which reduced ATP production and increased the lifespan of worms. Mechanistically, we discovered that chrysin and apigenin transiently inhibit mitochondrial respiration and induce an early ROS, and the lifespan-extending effect is dependent on transient ROS formation. We also show that AAK-2/AMPK, DAF-16/FOXO, and SKN-1/NRF-2 are required for chrysin or apigenin-mediated lifespan extension. Temporary increases in ROS levels trigger an adaptive response in a mitohormetic way, thereby increasing oxidative stress capacity and cellular metabolic adaptation, finally leading to longevity. Thus, chrysin and apigenin represent a class of compounds isolated from natural products that delay senescence and improve age-related diseases by inhibiting mitochondrial function and shed new light on the function of additional plant-derived polyphenols in enhancing health and delaying aging. Collectively, this work provides an avenue for pharmacological inhibition of mitochondrial function and the mechanism underlining their lifespan-extending properties.
    Keywords:  Aging; Apigenin; C. elegans; Chrysin; Mitohormesis; ROS
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.03.264
  13. Physiol Rev. 2023 Apr 06.
    Mitochondria in Health, Disease, and Ageing.
    John S Harrington, Stefan W Ryter, Maria Plataki, David R Price, Augustine M K Choi.
      Mitochondria are well-known as organelles responsible for the maintenance of cellular bioenergetics through the production of ATP. While oxidative phosphorylation may be their most important function, mitochondria are also integral for the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signaling, and apoptosis. Considering the breadth of their responsibilities, mitochondria are fundamental for cellular metabolism and homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger of disease. In this review, we provide a detailed overview of mitochondrial metabolism, cellular bioenergetics, mitochondrial dynamics, autophagy, mitochondrial damage-associated molecular patterns, mitochondria-mediated cell-death pathways, and how mitochondrial dysfunction at any of these levels is associated with disease pathogenesis. Mitochondria-dependent pathways may thereby represent an attractive therapeutic target for ameliorating human disease.
    Keywords:  Apoptosis; Inflammation; Mitochondria; Mitochondrial Dysfunction; Mitophagy
    DOI:  https://doi.org/10.1152/physrev.00058.2021
  14. Exp Gerontol. 2023 Apr 05. pii: S0531-5565(23)00086-4. [Epub ahead of print]176 112165
    Mediterranean diet and mitochondria: New findings.
    Francesco Pollicino, Nicola Veronese, Ligia J Dominguez, Mario Barbagallo.
      Mitochondria are subcellular organelles known for their central role in several energetic processes. Accumulating evidence supports a key role for mitochondria in the physiological response to both acute and chronic stress exposure, and, ultimately, the biological embedding of adversity in health and psychological functioning that increases the interest of these organelles in several medical conditions typical of older people. At the same time, Mediterranean diet (MedDiet) seems to affect the function of mitochondria further justifying the role of this diet in lowering the risk of negative health outcomes. In this review, we have elucidated the role of mitochondria in human diseases including the fundamental role in stress, aging, and neuropsychiatric and metabolic disorders. Overall, MedDiet can limit the production of free radicals, being rich in polyphenols. Moreover, MedDiet reduced mitochondrial reactive oxygen species (mtROS) production and ameliorated mitochondrial damage and apoptosis. Similarly, whole grains can maintain the mitochondrial respiration and membrane potential, finally improving mitochondrial function. Other components of MedDiet can have anti-inflammatory effects, again modulating mitochondrial function. For example, delphinidin (a flavonoid present in red wine and berries) restored the elevated level of mitochondrial respiration, mtDNA content, and complex IV activity; similarly, resveratrol and lycopene, present in grapefruits and tomatoes, exerted an anti-inflammatory effect modulating mitochondrial enzymes. Altogether, these findings support the notion that several positive effects of MedDiet can be mediated by a modulation in mitochondrial function indicating the necessity of further studies in human beings for finally confirming these findings.
    Keywords:  Dementia; Inflammation; Mediterranean diet; Metabolic syndrome; Mitochondria; Stress
    DOI:  https://doi.org/10.1016/j.exger.2023.112165
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