bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–08–13
seven papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Immune aging - A mechanism in autoimmune disease.
  2. Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response.
  3. Ginsenoside Rg1 improves anti-tumor efficacy of adoptive cell therapy by enhancing T cell effector functions.
  4. Glycogen synthase kinase 3 controls T-cell exhaustion by regulating NFAT activation.
  5. Hypoxia-sensing by the Histone Demethylase UTX ( KDM6A ) Controls Colitogenic CD4 + T cell Fate and Mucosal Inflammation.
  6. Role and Potential Mechanisms of Nicotinamide Mononucleotide in Aging.
  7. Glutaminolysis and peripheral CD4+ T cell differentiation: from mechanism to intervention strategy.
  1. Semin Immunol. 2023 Aug 03. pii: S1044-5323(23)00105-7. [Epub ahead of print]69 101814
    Immune aging - A mechanism in autoimmune disease.
    Yanyan Zheng, Qingxiang Liu, Jorg J Goronzy, Cornelia M Weyand.
      Evidence is emerging that the process of immune aging is a mechanism leading to autoimmunity. Over lifetime, the immune system adapts to profound changes in hematopoiesis and lymphogenesis, and progressively restructures in face of an ever-expanding exposome. Older adults fail to generate adequate immune responses against microbial infections and tumors, but accumulate aged T cells, B cells and myeloid cells. Age-associated B cells are highly efficient in autoantibody production. T-cell aging promotes the accrual of end-differentiated effector T cells with potent cytotoxic and pro-inflammatory abilities and myeloid cell aging supports a low grade, sterile and chronic inflammatory state (inflammaging). In pre-disposed individuals, immune aging can lead to frank autoimmune disease, manifesting with chronic inflammation and irreversible tissue damage. Emerging data support the concept that autoimmunity results from aging-induced failure of fundamental cellular processes in immune effector cells: genomic instability, loss of mitochondrial fitness, failing proteostasis, dwindling lysosomal degradation and inefficient autophagy. Here, we have reviewed the evidence that malfunctional mitochondria, disabled lysosomes and stressed endoplasmic reticula induce pathogenic T cells and macrophages that drive two autoimmune diseases, rheumatoid arthritis (RA) and giant cell arteritis (GCA). Recognizing immune aging as a risk factor for autoimmunity will open new avenues of immunomodulatory therapy, including the repair of malfunctioning mitochondria and lysosomes.
    Keywords:  Autoimmune disease; Giant cell arteritis; Immune aging; Rheumatoid arthritis; T cell aging
    DOI:  https://doi.org/10.1016/j.smim.2023.101814
  2. Nat Metab. 2023 Aug 07.
    Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response.
    J N Rashida Gnanaprakasam, Bhavana Kushwaha, Lingling Liu, Xuyong Chen, Siwen Kang, Tingting Wang, Teresa A Cassel, Christopher M Adams, Richard M Higashi, David A Scott, Gang Xin, Zihai Li, Jun Yang, Andrew N Lane, Teresa W-M Fan, Ji Zhang, Ruoning Wang.
      Robust and effective T cell immune surveillance and cancer immunotherapy require proper allocation of metabolic resources to sustain energetically costly processes, including growth and cytokine production. Here, we show that asparagine (Asn) restriction on CD8+ T cells exerted opposing effects during activation (early phase) and differentiation (late phase) following T cell activation. Asn restriction suppressed activation and cell cycle entry in the early phase while rapidly engaging the nuclear factor erythroid 2-related factor 2 (NRF2)-dependent stress response, conferring robust proliferation and effector function on CD8+ T cells during differentiation. Mechanistically, NRF2 activation in CD8+ T cells conferred by Asn restriction rewired the metabolic program by reducing the overall glucose and glutamine consumption but increasing intracellular nucleotides to promote proliferation. Accordingly, Asn restriction or NRF2 activation potentiated the T cell-mediated antitumoral response in preclinical animal models, suggesting that Asn restriction is a promising and clinically relevant strategy to enhance cancer immunotherapy. Our study revealed Asn as a critical metabolic node in directing the stress signaling to shape T cell metabolic fitness and effector functions.
    DOI:  https://doi.org/10.1038/s42255-023-00856-1
  3. Blood Sci. 2023 Jul;5(3): 170-179
    Ginsenoside Rg1 improves anti-tumor efficacy of adoptive cell therapy by enhancing T cell effector functions.
    Yue Liu, Lingna An, Chengfei Yang, Xiaoqi Wang, Ruihao Huang, Xi Zhang.
      Adoptive cell therapy (ACT) has emerged with remarkable efficacies for tumor immunotherapy. Chimeric antigen receptor (CAR) T cell therapy, as one of most promising ACTs, has achieved prominent effects in treating malignant hematological tumors. However, the insufficient killing activity and limited persistence of T cells in the immunosuppressive tumor microenvironment limit the further application of ACTs for cancer patients. Many studies have focused on improving cytotoxicity and persistence of T cells to achieve improved therapeutic effects. In this study, we explored the potential function in ACT of ginsenoside Rg1, the main pharmacologically active component of ginseng. We introduced Rg1 during the in vitro activation and expansion phase of T cells, and found that Rg1 treatment upregulated two T cell activation markers, CD69 and CD25, while promoting T cell differentiation towards a mature state. Transcriptome sequencing revealed that Rg1 influenced T cell metabolic reprogramming by strengthening mitochondrial biosynthesis. When co-cultured with tumor cells, Rg1-treated T cells showed stronger cytotoxicity than untreated cells. Moreover, adding Rg1 to the culture endowed CAR-T cells with enhanced anti-tumor efficacy. This study suggests that ginsenoside Rg1 provides a potential approach for improving the anti-tumor efficacy of ACT by enhancing T cell effector functions.
    Keywords:  Adoptive cell therapy; Anti-tumor efficacy; CAR-T; Ginsenoside Rg1; Metabolic regulation
    DOI:  https://doi.org/10.1097/BS9.0000000000000165
  4. Cell Mol Immunol. 2023 Aug 09.
    Glycogen synthase kinase 3 controls T-cell exhaustion by regulating NFAT activation.
    Yubing Fu, Jinjia Wang, Chenfeng Liu, Kunyu Liao, Xianjun Gao, Ronghan Tang, Binbin Fan, Yazhen Hong, Nengming Xiao, Changchun Xiao, Wen-Hsien Liu.
      Cellular immunity mediated by CD8+ T cells plays an indispensable role in bacterial and viral clearance and cancers. However, persistent antigen stimulation of CD8+ T cells leads to an exhausted or dysfunctional cellular state characterized by the loss of effector function and high expression of inhibitory receptors during chronic viral infection and in tumors. Numerous studies have shown that glycogen synthase kinase 3 (GSK3) controls the function and development of immune cells, but whether GSK3 affects CD8+ T cells is not clearly elucidated. Here, we demonstrate that mice with deletion of Gsk3α and Gsk3β in activated CD8+ T cells (DKO) exhibited decreased CTL differentiation and effector function during acute and chronic viral infection. In addition, DKO mice failed to control tumor growth due to the upregulated expression of inhibitory receptors and augmented T-cell exhaustion in tumor-infiltrating CD8+ T cells. Strikingly, anti-PD-1 immunotherapy substantially restored tumor rejection in DKO mice. Mechanistically, GSK3 regulates T-cell exhaustion by suppressing TCR-induced nuclear import of NFAT, thereby in turn dampening NFAT-mediated exhaustion-related gene expression, including TOX/TOX2 and PD-1. Thus, we uncovered the molecular mechanisms underlying GSK3 regulation of CTL differentiation and T-cell exhaustion in anti-tumor immune responses.
    Keywords:  Anti-tumor immunity; GSK3; Inhibitory receptors; T-cell exhaustion; Viral infection
    DOI:  https://doi.org/10.1038/s41423-023-01075-0
  5. bioRxiv. 2023 Jul 29. pii: 2023.07.27.550746. [Epub ahead of print]
    Hypoxia-sensing by the Histone Demethylase UTX ( KDM6A ) Controls Colitogenic CD4 + T cell Fate and Mucosal Inflammation.
    Mandy I Cheng, Lee Hong, Bryan Chen, Scott Chin, Christopher R Luthers, Christian Bustillos, Shehzad Z Sheikh, Maureen A Su.
      Hypoxia is a feature of inflammatory conditions [e.g., inflammatory bowel disease (IBD)] and can exacerbate tissue damage in these diseases. To counteract hypoxia's deleterious effects, adaptive responses have evolved which protect against hypoxia-associated tissue injury. To date, much attention has focused on hypoxia-activated HIF (hypoxia-inducible factor) transcription factors in these responses. However, recent work has identified epigenetic regulators that are also oxygen-sensitive, but their role in adaptation to hypoxic inflammation is currently unclear. Here, we show that the oxygen-sensing epigenetic regulator UTX is a critical modulator of colitis severity. Unlike HIF transcription factors that act on gut epithelial cells, UTX functions in colitis through its effects on immune cells. Hypoxia results in decreased CD4 + T cell IFN-γ production and increased CD4 + regulatory T cells, and these findings are recapitulated by T cell-specific UTX deficiency. Hypoxia impairs the histone demethylase activity of UTX, and loss of UTX function leads to accumulation of repressive H3K27me3 epigenetic marks at IL12/STAT4 pathway genes ( Il12rb2, Tbx21, and Ifng ). In a colitis mouse model, T cell-specific UTX deletion ameliorates colonic inflammation, protects against weight loss, and increases survival. Together these findings implicate UTX's oxygen-sensitive histone demethylase activity in mediating protective, hypoxia-induced pathways in colitis.
    DOI:  https://doi.org/10.1101/2023.07.27.550746
  6. Aging Dis. 2023 Jul 27.
    Role and Potential Mechanisms of Nicotinamide Mononucleotide in Aging.
    Sajid Ur Rahman, Abdul Qadeer, Ziyun Wu.
      Nicotinamide adenine dinucleotide (NAD+) has recently attracted much attention due to its role in aging and lifespan extension. NAD+ directly and indirectly affects many cellular processes, including metabolic pathways, DNA repair, and immune cell activities. These mechanisms are critical for maintaining cellular homeostasis. However, the decline in NAD+ levels with aging impairs tissue function, which has been associated with several age-related diseases. In fact, the aging population has been steadily increasing worldwide, and it is important to restore NAD+ levels and reverse or delay these age-related disorders. Therefore, there is an increasing demand for healthy products that can mitigate aging, extend lifespan, and halt age-related consequences. In this case, several studies in humans and animals have targeted NAD+ metabolism with NAD+ intermediates. Among them, nicotinamide mononucleotide (NMN), a precursor in the biosynthesis of NAD+, has recently received much attention from the scientific community for its anti-aging properties. In model organisms, ingestion of NMN has been shown to improve age-related diseases and probably delay death. Here, we review aspects of NMN biosynthesis and the mechanism of its absorption, as well as potential anti-aging mechanisms of NMN, including recent preclinical and clinical tests, adverse effects, limitations, and perceived challenges.
    DOI:  https://doi.org/10.14336/AD.2023.0519-1
  7. Front Immunol. 2023 ;14 1221530
    Glutaminolysis and peripheral CD4+ T cell differentiation: from mechanism to intervention strategy.
    Tong Liu, Shaohua Ren, Chenglu Sun, Pengyu Zhao, Hao Wang.
      To maintain the body's regular immune system, CD4+ T cell homeostasis is crucial, particularly T helper (Th1, Th17) cells and T regulatory (Treg) cells. Abnormally differentiated peripheral CD4+ T cells are responsible for the occurrence and development of numerous diseases, including autoimmune diseases, transplantation rejection, and irritability. Searching for an effective interventional approach to control this abnormal differentiation is therefore especially important. As immunometabolism progressed, the inherent metabolic factors underlying the immune cell differentiation have gradually come to light. Mounting number of studies have revealed that glutaminolysis plays an indelible role in the differentiation of CD4+ T cells. Besides, alterations in the glutaminolysis can also lead to changes in the fate of peripheral CD4+ T cells. All of this indicate that the glutaminolysis pathway has excellent potential for interventional regulation of CD4+ T cells differentiation. Here, we summarized the process by which glutaminolysis regulates the fate of CD4+ T cells during differentiation and further investigated how to reshape abnormal CD4+ T cell differentiation by targeting glutaminolysis.
    Keywords:  CD4 + T cells; T cell differentiation; glutaminolysis; immunometabolism; intervention strategy
    DOI:  https://doi.org/10.3389/fimmu.2023.1221530
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