bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023‒10‒01
twelve papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Negative Influence of Aging on Differentiation and Proliferation of CD8+ T-Cells in Dogs.
  2. Tissue-Specific Dependence of Th1 Cells on the Amino Acid Transporter SLC38A1 in Inflammation.
  3. Potential role of mesenchymal stem cells in T cell aging.
  4. Role of cytokine in malignant T-cell metabolism and subsequent alternation in T-cell tumor microenvironment.
  5. Erucic acid improves the progress of pregnancy complicated with systemic lupus erythematosus by inhibiting the effector function of CD8+ T cells.
  6. Towards a better preclinical cancer model - human immune aging in humanized mice.
  7. Low dietary fiber intake impairs small intestinal Th17 and intraepithelial T cell development over generations.
  8. Ginsenoside F1-Mediated Telomere Preservation Delays Cellular Senescence.
  9. The NADase CD38 May not dictate NAD levels in brain Mitochondria of aged mice but regulates hydrogen peroxide generation.
  10. Intracellular K + limits T cell exhaustion and preserves antitumor function.
  11. Reciprocal transmission of activating and inhibitory signals and cell fate in regenerating T cells.
  12. Ibrutinib directly reduces CD8+T cell exhaustion independent of BTK.
  1. Vet Sci. 2023 Aug 25. pii: 541. [Epub ahead of print]10(9):
    Negative Influence of Aging on Differentiation and Proliferation of CD8+ T-Cells in Dogs.
    Akinori Yamauchi, Sho Yoshimoto, Ayano Kudo, Satoshi Takagi.
      Immunosenescence is an age-related change in the immune system characterized by a reduction in naïve T-cells and an impaired proliferative capacity of CD8+ T-cells in older individuals. Recent research revealed the crucial impact of immunosenescence on the development and control of cancer, and aging is one of the causes that diminish the therapeutic efficacy of cancer immunotherapies targeting CD8+ T-cell activation. Despite dog cancer being defined as an age-related disease, there are few fundamental understandings regarding the relationship between aging and the canine immune system. Therefore, we aimed to elucidate the characteristics of immunosenescence in dogs and analyzed the effects of aging on the differentiation status and proliferation of canine CD8+ T cells using T-cell specific stimulation with anti-canine CD3/CD28 antibody-coated beads and interleukin-2. As a result, we found that older dogs have a lower proliferative capacity of CD8+ T-cells and a reduction in the naïve subset in their peripheral blood. Further analysis showed that older dogs had attenuated proliferation of the effector and central memory subsets. These results indicate the importance of maintaining less differentiated subsets to expand CD8+ T-cells in dogs and provide helpful insight into the development of dog immune therapies that require T-cell expansion ex vivo.
    Keywords:  CD8+ T-cell; T-cell proliferation; T-cell senescence; T-cell subsets; aging; dog; immune senescence
    DOI:  https://doi.org/10.3390/vetsci10090541
  2. bioRxiv. 2023 Sep 13. pii: 2023.09.13.557496. [Epub ahead of print]
    Tissue-Specific Dependence of Th1 Cells on the Amino Acid Transporter SLC38A1 in Inflammation.
    Ayaka Sugiura, Katherine L Beier, Channing Chi, Darren R Heintzman, Xiang Ye, Melissa M Wolf, Andrew R Patterson, Jacqueline-Yvonne Cephus, Hanna S Hong, Costas A Lyssiotis, Dawn C Newcomb, Jeffrey C Rathmell.
      Amino acid (AA) uptake is essential for T cell metabolism and function, but how tissue sites and inflammation affect CD4 + T cell subset requirements for specific AA remains uncertain. Here we tested CD4 + T cell AA demands with in vitro and multiple in vivo CRISPR screens and identify subset- and tissue-specific dependencies on the AA transporter SLC38A1 (SNAT1). While dispensable for T cell persistence and expansion over time in vitro and in vivo lung inflammation, SLC38A1 was critical for Th1 but not Th17 cell-driven Experimental Autoimmune Encephalomyelitis (EAE) and contributed to Th1 cell-driven inflammatory bowel disease. SLC38A1 deficiency reduced mTORC1 signaling and glycolytic activity in Th1 cells, in part by reducing intracellular glutamine and disrupting hexosamine biosynthesis and redox regulation. Similarly, pharmacological inhibition of SLC38 transporters delayed EAE but did not affect lung inflammation. Subset- and tissue-specific dependencies of CD4 + T cells on AA transporters may guide selective immunotherapies.HIGHLIGHTS: T cells dynamically regulate glutamine amino acid transporters when activatedSLC38A1 supports Th1 cell mTORC1 and proliferation by redox and hexosamine pathwaysTargeting SLC38A1 does not affect lung inflammation but delays IBD and EAENutrient transporter needs of T cell subsets vary based on disease and tissue site.
    DOI:  https://doi.org/10.1101/2023.09.13.557496
  3. J Mol Med (Berl). 2023 Sep 26.
    Potential role of mesenchymal stem cells in T cell aging.
    Xianmei Zhong, Jie Chen, Bo Wen, Xu Wu, Mingxing Li, Fukuan Du, Yu Chen, Shuai Deng, Yueshui Zhao, Jing Shen, Zhangang Xiao.
      Immunosenescence occurs with progressive age. T cell aging is manifested by immunodeficiency and inflammation. The main mechanisms are thymic involution, mitochondrial dysfunction, genetic and epigenetic alterations, loss of protein stability, reduction of T cell receptor (TCR) repertoire, naïve-memory T cell ratio imbalance, T cell senescence, and lack of effector plasticity. Mesenchymal stem cells (MSCs) are thought to hold great potential as anti-aging therapy. However, the role of MCSs in T cell aging remains elusive. This review makes a tentative summary of the potential role of MSCs in the protection against T cell aging. It might provide a new idea to intervene in the aging of the immune system.
    Keywords:  Aging; Immune; Mesenchymal stem cells; T cell
    DOI:  https://doi.org/10.1007/s00109-023-02371-y
  4. Front Oncol. 2023 ;13 1235711
    Role of cytokine in malignant T-cell metabolism and subsequent alternation in T-cell tumor microenvironment.
    Megha Yadav, Blessi N Uikey, Shantnu Singh Rathore, Priyanka Gupta, Diksha Kashyap, Chanchal Kumar, Dhananjay Shukla, Vijayamahantesh, Arvind Singh Chandel, Bharti Ahirwar, Ashish Kumar Singh, Shashi Shekhar Suman, Amit Priyadarshi, Ajay Amit.
      T cells are an important component of adaptive immunity and T-cell-derived lymphomas are very complex due to many functional sub-types and functional elasticity of T-cells. As with other tumors, tissues specific factors are crucial in the development of T-cell lymphomas. In addition to neoplastic cells, T- cell lymphomas consist of a tumor micro-environment composed of normal cells and stroma. Numerous studies established the qualitative and quantitative differences between the tumor microenvironment and normal cell surroundings. Interaction between the various component of the tumor microenvironment is crucial since tumor cells can change the microenvironment and vice versa. In normal T-cell development, T-cells must respond to various stimulants deferentially and during these courses of adaptation. T-cells undergo various metabolic alterations. From the stage of quiescence to attention of fully active form T-cells undergoes various stage in terms of metabolic activity. Predominantly quiescent T-cells have ATP-generating metabolism while during the proliferative stage, their metabolism tilted towards the growth-promoting pathways. In addition to this, a functionally different subset of T-cells requires to activate the different metabolic pathways, and consequently, this regulation of the metabolic pathway control activation and function of T-cells. So, it is obvious that dynamic, and well-regulated metabolic pathways are important for the normal functioning of T-cells and their interaction with the microenvironment. There are various cell signaling mechanisms of metabolism are involved in this regulation and more and more studies have suggested the involvement of additional signaling in the development of the overall metabolic phenotype of T cells. These important signaling mediators include cytokines and hormones. The impact and role of these mediators especially the cytokines on the interplay between T-cell metabolism and the interaction of T-cells with their micro-environments in the context of T-cells lymphomas are discussed in this review article.
    Keywords:  T cell lymphoma; cell signaling; cytokine; metabolism; tumor micro environment
    DOI:  https://doi.org/10.3389/fonc.2023.1235711
  5. MedComm (2020). 2023 Oct;4(5): e382
    Erucic acid improves the progress of pregnancy complicated with systemic lupus erythematosus by inhibiting the effector function of CD8+ T cells.
    Yanling Chang, Meng Jiang, You Wang, Qiong Fu, Sihan Lin, Jiayue Wu, Wen Di.
      Pathogenic CD8+ T cells are pivotal contributors to the onset of systemic lupus erythematosus (SLE). Erucic acid (EA) has been proven to have anti-inflammatory activity. However, the capacity of EA to regulate pathogenic CD8+ T cells in the context of pregnancy complicated with SLE (pSLE) remains unclear. In our investigation, we observed augmented CD8+ T cell effector function juxtaposed with diminished EA levels in pSLE patients relative to healthy pregnant controls. Significantly, plasma EA levels exhibited a negative correlation with the severity of pSLE-associated complications. In blood from patients with pSLE, EA inhibited the effector function of CD8+ T cells, concurrently dampening the maintenance of stem cell-like memory CD8+ T cells. Mechanistically, EA orchestrated the inhibition of CD8+ T cell effector function by impeding signal transducer and activator of transcription 3 phosphorylation and promoting ferroptosis. Moreover, EA supplementation in pregnant MRL/lpr mice manifested as the attenuation of uterine CD8+ T cell effector function, culminating in the mitigation of placental pathological damage. Our findings uncover the immune response modulatory effects of EA upon pathogenic CD8+ cells, thereby unveiling new perspectives for therapeutic strategies targeting pSLE patients.
    Keywords:  CD8+ T cells; erucic acid; pregnancy; systemic lupus erythematosus
    DOI:  https://doi.org/10.1002/mco2.382
  6. Immun Ageing. 2023 Sep 27. 20(1): 49
    Towards a better preclinical cancer model - human immune aging in humanized mice.
    Joel H L Tan, You Yi Hwang, Hui Xian Chin, Min Liu, Sue Yee Tan, Qingfeng Chen.
      BACKGROUND: Preclinical models are often used for cancer studies and evaluation of novel therapeutics. The relevance of these models has vastly improved with mice bearing a human immune system, especially in the context of immunotherapy. Nonetheless, cancer is an age-related disease, and studies often overlook the effects of aging. Here we have established a humanized mouse model of human immune aging to investigate the role of this phenomenon on liver tumor dynamics.METHODS: Multiple organs and tissues (blood, thymus, lung, liver, spleen and bone marrow) were harvested from NOD-scid IL2rγ-/- (NIKO) mice reconstituted with human immune cells, over a period of 60 weeks post-birth, for immune profiling. Young and aging immune cells were compared for transcriptomic changes and functional differences. Effect of immune aging was investigated in a liver cancer humanized mouse model.
    RESULTS: Focusing on the T cell population, which is central to cancer immunosurveillance and immunotherapy, we showed that the proportion of naïve T cells declined while memory subsets and senescent-like cells increased with age. RNA-sequencing revealed that downregulated genes were related to immune responses and processes, and this was corroborated by reduced cytokine production in aging T cells. Finally, we showed faster liver tumor growth in aging than younger humanized mice, which could be attributed to specific pathways of aging T cell exhaustion.
    CONCLUSION: Our work improves on existing humanized (immune) mouse model and highlights the importance of considering immune aging in liver cancer modeling.
    Keywords:  Cancer; Humanized mice; Immune aging; T cells
    DOI:  https://doi.org/10.1186/s12979-023-00374-4
  7. Cell Rep. 2023 Sep 27. pii: S2211-1247(23)01152-X. [Epub ahead of print]42(10): 113140
    Low dietary fiber intake impairs small intestinal Th17 and intraepithelial T cell development over generations.
    Charlotte J Royer, Naomi Rodriguez-Marino, Madelyn D Yaceczko, Dormarie E Rivera-Rodriguez, Thomas R Ziegler, Luisa Cervantes-Barragan.
      Dietary fiber strongly impacts the microbiota. Here, we show that a low-fiber diet changes the small intestinal (SI) microbiota and impairs SI Th17, TCRαβ+CD8αβ+ and TCRαβ+CD8αα+ intraepithelial T cell development. We restore T cell development with dietary fiber supplementation, but this defect becomes persistent over generations with constant low-fiber diets. Offspring of low-fiber diet-fed mice have reduced SI T cells even after receiving a fiber-rich diet due to loss of bacteria important for T cell development. In these mice, only a microbiota transplant from a fiber-rich diet-fed mouse and a fiber-rich diet can restore T cell development. Low-fiber diets reduce segmented filamentous bacteria (SFB) abundance, impairing its vertical transmission. SFB colonization and a fiber-rich diet partially restore T cell development. Finally, we observe that low-fiber diet-induced T cell defects render mice more susceptible to Citrobacter rodentium infection. Together, these results demonstrate the importance of fiber to microbiota vertical transmission and host immune system development.
    Keywords:  CD8αβ(+) IEL; CP: Immunology; CP: Microbiology; IEL T cells; Th17; dietary fiber; interleukin 17; intraepithelial; microbiota; segmented filamentous bacteria
    DOI:  https://doi.org/10.1016/j.celrep.2023.113140
  8. Int J Mol Sci. 2023 Sep 19. pii: 14241. [Epub ahead of print]24(18):
    Ginsenoside F1-Mediated Telomere Preservation Delays Cellular Senescence.
    Jingang Hou, Yeejin Yun, Byeongmin Jeon, Jongin Baek, Sunchang Kim.
      Telomeres play pivotal roles in processes closely related to somatic senescence and aging, making them a compelling target for interventions aimed at combating aging and age-related pathologies. Ginsenoside, a natural compound, has emerged as a potential remedy for promoting healthy aging, yet how it protects telomeres remains incompletely understood. Here, we show that treatment of F1 can effectively restore the level of TRF2, thereby preserving telomere integrity. This restoration leads to inhibition of the DNA damage response and improvements in mitochondrial function and, ultimately, delays in cellular senescence. Conversely, depletion of TRF2 causes mitochondrial dysfunction, accompanied by increased oxidative stress, autophagy inhibition, insufficient energy metabolism, and the onset of cellular senescence. These observations underscore the critical role of TRF2 in maintaining telomere integrity and direct association with the initiation of cellular senescence. We conduct a further analysis, suggesting F1 could bind in proximity to the TRF2 heterodimer interface, potentially enhancing dimerization stability. These findings suggest that F1 may be a promising natural remedy for anti-aging, and restoring TRF2 could potentially prevent telomere-dependent diseases commonly associated with the aging process.
    Keywords:  TRF2; ginsenoside F1; mitochondria; oxidative stress; senescence
    DOI:  https://doi.org/10.3390/ijms241814241
  9. Free Radic Biol Med. 2023 Sep 27. pii: S0891-5849(23)00660-3. [Epub ahead of print]
    The NADase CD38 May not dictate NAD levels in brain Mitochondria of aged mice but regulates hydrogen peroxide generation.
    Juliana Camacho-Pereira, Leonardo Osbourne Lai de Souza, Marina Santos Chichierchio, Camila Rodrigues Chaves, Luiza de Souza Lomba, Manoel Fonseca Santos Oliveira, Daniel Carvalho Mendonça, Thaia da Silva Rodrigues, Antonio Galina.
      Aging is a time-related functional decline that affects many species. One of the hallmarks of aging is mitochondrial dysfunction, which leads to metabolic decline. The NAD decline during aging, in several tissues, correlates with increase in NADase activity of CD38. Knock out or pharmacological inhibition of CD38 activity can rescue mitochondrial function in several tissues, however, the role of CD38 in controlling NAD levels and metabolic function in the aging brain is unknown. In this work, we investigated CD38 NADase activity controlling NAD levels and mitochondrial function in mice brain with aging. We demonstrate that NADase activity of CD38 does not dictate NAD total levels in brain of aging mice and does not control mitochondrial oxygen consumption nor other oxygen parameters markers of mitochondrial dysfunction. However, for the first time we show that CD38 regulates hydrogen peroxide (H2O2) generation, one of the reactive oxygen species (ROS) in aging brain, through regulation of pyruvate dehydrogenase and alfa-ketoglutarate dehydrogenase, as mitochondria H2O2 leakage sites. The effect may be related to mitochondrial calcium handling differences in CD38 absence. Our study highlights a novel role of CD38 in brain energy metabolism and aging.
    Keywords:  Aging; Brain mitochondrial metabolism; CD38; Calcium uptake; NAD metabolism; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.035
  10. bioRxiv. 2023 Sep 15. pii: 2023.09.13.556997. [Epub ahead of print]
    Intracellular K + limits T cell exhaustion and preserves antitumor function.
    Camille Collier, Kelly Wucherer, Matthew McWhorter, Chelsea Jenkins, Alexandra Bartlett, Rahul Roychoudhuri, Robert Eil.
      The cancer-killing activity of T cells is often compromised within tumors, allowing disease progression. We previously found that intratumoral elevations in extracellular K + related to ongoing cell death constrained CD8 + T cell Akt-mTOR signaling and effector function (1,2). To alleviate K + mediated T cell suppression, we pursued genetic means to lower intracellular K + . Transcriptomic analysis of CD8 + T cells demonstrated the Na + /K + ATPase to be robustly and dynamically expressed. CRISPR-Cas9 mediated deletion of the catalytic alpha subunit of the Na + /K + ATPase lowered intracellular K + but produced tonic hyperactivity in multiple signal transduction cascades along with the acquisition of co-inhibitory receptors and terminal differentiation in mouse and human CD8 + T cells. Mechanistically, Na + /K + ATPase disruption led to ROS accumulation due to depletion of intracellular K + in T cells. Antioxidant treatment or high K + media prevented Atp1a1 deficient T cells from exhausted T (T Ex ) cell formation. Consistent with transcriptional and proteomic data suggesting a T Ex cell phenotype, T cells lacking Atp1a1 had compromised persistence and antitumor activity in a syngeneic model of orthotopic murine melanoma. Translational application of these findings will include efforts to lower intracellular K + while limiting ROS accumulation within tumor specific T cells.Synopsis: High extracellular K + (↑[K + ] e ) is found within tumors and suppresses T cell effector function. Collier et al. find that deletion of the Na + /K + ATPase in T cells lowers intracellular K + and promotes ROS accumulation, tonic signal transduction and T cell exhaustion owing to ROS accumulation. Engineering T cell ion transport is an important consideration for cancer immunotherapy.
    DOI:  https://doi.org/10.1101/2023.09.13.556997
  11. Cell Rep. 2023 Sep 26. pii: S2211-1247(23)01167-1. [Epub ahead of print]42(10): 113155
    Reciprocal transmission of activating and inhibitory signals and cell fate in regenerating T cells.
    Peter H Wang, Robert S Washburn, Dylan L Mariuzza, Wen-Hsuan W Lin, Amanda L Gill, Rafi Ahmed, Steven L Reiner.
      The ability of activated progenitor T cells to self-renew while producing differentiated effector cell descendants may underlie immunological memory and persistent responses to ongoing infection. The nature of stem-like T cells responding to cancer and during treatment with immunotherapy is not clear. The subcellular organization of dividing progenitor CD8+ T cells from mice challenged with syngeneic tumors is examined here. Three-dimensional microscopy reveals an activating hub composed of polarized CD3, CD28, and phosphatidylinositol 3-kinase (PI3K) activity at the putative immunological synapse with an inhibitory hub composed of polarized PD-1 and CD73 at the opposite pole of mitotic blasts. Progenitor T cells from untreated and inhibitory checkpoint blockade-treated mice yield a differentiated TCF1- daughter cell, which inherits the PI3K activation hub, alongside a discordantly fated, self-renewing TCF1+ sister cell. Dynamic organization of opposite activating and inhibitory signaling poles in mitotic lymphocytes may account for the enigmatic durability of specific immunity.
    Keywords:  CD8(+) T cell; CP: Cell biology; PD-1; PI3K; TCF1; asymmetric cell division; cancer immunotherapy; self-renewal; stem cell
    DOI:  https://doi.org/10.1016/j.celrep.2023.113155
  12. Front Immunol. 2023 ;14 1201415
    Ibrutinib directly reduces CD8+T cell exhaustion independent of BTK.
    Ling Li, Manzhi Zhao, Caoimhe H Kiernan, Melisa D Castro Eiro, Marjan van Meurs, Inge Brouwers-Haspels, Merel E P Wilmsen, Dwin G B Grashof, Harmen J G van de Werken, Rudi W Hendriks, Yvonne M Mueller, Peter D Katsikis.
      Introduction: Cytotoxic CD8+ T cell (CTL) exhaustion is a dysfunctional state of T cells triggered by persistent antigen stimulation, with the characteristics of increased inhibitory receptors, impaired cytokine production and a distinct transcriptional profile. Evidence from immune checkpoint blockade therapy supports that reversing T cell exhaustion is a promising strategy in cancer treatment. Ibrutinib, is a potent inhibitor of BTK, which has been approved for the treatment of chronic lymphocytic leukemia. Previous studies have reported improved function of T cells in ibrutinib long-term treated patients but the mechanism remains unclear. We investigated whether ibrutinib directly acts on CD8+ T cells and reinvigorates exhausted CTLs.Methods: We used an established in vitro CTL exhaustion system to examine whether ibrutinib can directly ameliorate T cell exhaustion. Changes in inhibitory receptors, transcription factors, cytokine production and killing capacity of ibrutinib-treated exhausted CTLs were detected by flow cytometry. RNA-seq was performed to study transcriptional changes in these cells. Btk deficient mice were used to confirm that the effect of ibrutinib was independent of BTK expression.
    Results: We found that ibrutinib reduced exhaustion-related features of CTLs in an in vitro CTL exhaustion system. These changes included decreased inhibitory receptor expression, enhanced cytokine production, and downregulation of the transcription factor TOX with upregulation of TCF1. RNA-seq further confirmed that ibrutinib directly reduced the exhaustion-related transcriptional profile of these cells. Importantly, using btk deficient mice we showed the effect of ibrutinib was independent of BTK expression, and therefore mediated by one of its other targets.
    Discussion: Our study demonstrates that ibrutinib directly ameliorates CTL exhaustion, and provides evidence for its synergistic use with cancer immunotherapy.
    Keywords:  BTK inhibitor; CD8+ T cells; T-cell exhaustion; ibrutinib; immune checkpoint blockade
    DOI:  https://doi.org/10.3389/fimmu.2023.1201415
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