bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022‒08‒07
thirteen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research
  1. Tumor microenvironmental signals reshape chromatin landscapes to limit the functional potential of exhausted T cells.
  2. T cell metabolism as interpreted in obesity-associated inflammation.
  3. Protein Kinase CK2 Controls CD8+ T Cell Effector and Memory Function during Infection.
  4. The Transcription Factor Zfp335 Promotes Differentiation and Persistence of Memory CD8+ T Cells by Regulating TCF-1.
  5. Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers.
  6. Mitochondrial Deep Dive into Hematopoietic Stem Cell Dormancy: Not Much Glycolysis but Plenty of Sluggish Lysosomes.
  7. Editorial: The role of immunometabolism in autoimmune mediated and autoinflammatory disorders.
  8. mTOR Participates in the Formation, Maintenance, and Function of Memory CD8+T Cells Regulated by Glycometabolism.
  9. Nrf2 as a regulator of mitochondrial function: Energy metabolism and beyond.
  10. Vitamin A, systemic T-cells, and the eye: Focus on degenerative retinal disease.
  11. Iron controls T helper cell pathogenicity by promoting glucose metabolism in autoimmune myopathy.
  12. Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation.
  13. A novel strategy to fuel cancer immunotherapy: targeting glucose metabolism to remodel the tumor microenvironment.
  1. Sci Immunol. 2022 Aug 05. 7(74): eabj9123
    Tumor microenvironmental signals reshape chromatin landscapes to limit the functional potential of exhausted T cells.
    B Rhodes Ford, Paolo D A Vignali, Natalie L Rittenhouse, Nicole E Scharping, Ronal Peralta, Konstantinos Lontos, Andrew T Frisch, Greg M Delgoffe, Amanda C Poholek.
      Response rates to immunotherapy in solid tumors remain low due in part to the elevated prevalence of terminally exhausted T cells, a hypofunctional differentiation state induced through persistent antigen and stress signaling. However, the mechanisms promoting progression to terminal exhaustion in the tumor remain undefined. Using the low-input chromatin immunoprecipitation sequencing method CUT&RUN, we profiled the histone modification landscape of tumor-infiltrating CD8+ T cells throughout differentiation. We found that terminally exhausted T cells had unexpected chromatin features that limit their transcriptional potential. Terminally exhausted T cells had a substantial fraction of active chromatin, including active enhancers enriched for bZIP/AP-1 transcription factor motifs that lacked correlated gene expression, which was restored by immunotherapeutic costimulatory signaling. Reduced transcriptional potential was also driven by an increase in histone bivalency, which we linked directly to hypoxia exposure. Enforced expression of the hypoxia-insensitive histone demethylase Kdm6b was sufficient to overcome hypoxia, increase function, and promote antitumor immunity. Our study reveals the specific epigenetic changes mediated by histone modifications during T cell differentiation that support exhaustion in cancer, highlighting that their altered function is driven by improper costimulatory signals and environmental factors. These data suggest that even terminally exhausted T cells may remain competent for transcription in settings of increased costimulatory signaling and reduced hypoxia.
    DOI:  https://doi.org/10.1126/sciimmunol.abj9123
  2. Endocrinology. 2022 Aug 06. pii: bqac124. [Epub ahead of print]
    T cell metabolism as interpreted in obesity-associated inflammation.
    Leena P Bharath, Samantha Hart, Barbara S Nikolajczyk.
      The appreciation of metabolic regulation of T cell function has exploded over the past decade, as has our understanding of how inflammation fuels comorbidities of obesity, including type 2 diabetes. The likelihood that obesity fundamentally alters T cell metabolism and thus chronic obesity-associated inflammation is high, but studies testing causal relationships remain under-represented. We searched PubMed for key words including mitochondria, obesity, T cell, type 2 diabetes, cristae, fission, fusion, redox, and reactive oxygen species to identify foundational and more recent studies that address these topics or cite foundational work. We investigated primary papers cited by reviews found in these searches, and highlight recent work with >100 citations to illustrate the state of the art in understanding mechanisms that control metabolism and thus function of various T cell subsets in obesity. However, "popularity" of a paper over the first 5 years after publication cannot assess long-term impact; thus some likely important work with fewer citations is also highlighted. We feature studies of human cells, supplementing with studies from animal models that suggest future directions for human cell research. This approach identified gaps in the literature that will need filled before we can estimate efficacy of mitochondria-targeted drugs in clinical trials to alleviate pathogenesis of obesity-associated inflammation.
    Keywords:  human; mitochondria; prediabetes; type 2 diabetes
    DOI:  https://doi.org/10.1210/endocr/bqac124
  3. J Immunol. 2022 Aug 01. pii: ji2101080. [Epub ahead of print]
    Protein Kinase CK2 Controls CD8+ T Cell Effector and Memory Function during Infection.
    Wei Yang, Hairong Wei, Gloria A Benavides, William J Turbitt, Jessica A Buckley, Xiaosen Ouyang, Lianna Zhou, Jianhua Zhang, Laurie E Harrington, Victor M Darley-Usmar, Hongwei Qin, Etty N Benveniste.
      Protein kinase CK2 is a serine/threonine kinase composed of two catalytic subunits (CK2α and/or CK2α') and two regulatory subunits (CK2β). CK2 promotes cancer progression by activating the NF-κB, PI3K/AKT/mTOR, and JAK/STAT pathways, and also is critical for immune cell development and function. The potential involvement of CK2 in CD8+ T cell function has not been explored. We demonstrate that CK2 protein levels and kinase activity are enhanced upon mouse CD8+ T cell activation. CK2α deficiency results in impaired CD8+ T cell activation and proliferation upon TCR stimulation. Furthermore, CK2α is involved in CD8+ T cell metabolic reprogramming through regulating the AKT/mTOR pathway. Lastly, using a mouse Listeria monocytogenes infection model, we demonstrate that CK2α is required for CD8+ T cell expansion, maintenance, and effector function in both primary and memory immune responses. Collectively, our study implicates CK2α as an important regulator of mouse CD8+ T cell activation, metabolic reprogramming, and differentiation both in vitro and in vivo.
    DOI:  https://doi.org/10.4049/jimmunol.2101080
  4. J Immunol. 2022 Aug 01. pii: ji2200026. [Epub ahead of print]
    The Transcription Factor Zfp335 Promotes Differentiation and Persistence of Memory CD8+ T Cells by Regulating TCF-1.
    Haiyan Liu, Xin Wang, Renyi Ding, Anjun Jiao, Huiqiang Zheng, Cangang Zhang, Zhao Feng, Yanhong Su, Xiaofeng Yang, Lei Lei, Lina Sun, Lianjun Zhang, Chenming Sun, Baojun Zhang.
      Memory CD8+ T cells play an essential role in providing effective and lifelong protection against pathogens. Comprehensive transcriptional and epigenetic networks are involved in modulating memory T cell development, but the molecular regulations of CD8+ memory T cell formation and long-term persistence remain largely unknown. In this study, we show that zinc finger protein 335 (Zfp335) is indispensable for CD8+ T cell memory establishment and maintenance during acute infections. Mice with Zfp335 deletion in CD8+ T cells exhibit a significant reduction of memory T cells and memory precursor cells in the contraction phase. Zfp335 deficiency in CD8+ T cells resulted in decreased expression of memory featured genes Eomes and IL-2Rβ, leading to a loss of memory identity and an increase of apoptosis in response to IL-7 and IL-15. Mechanistically, Zfp335 directly binds to and regulates TCF-1, known to be critical for memory T cell development. Importantly, overexpression TCF-1 could rescue the defects in the survival of both CD8+ memory precursors and memory T cells caused by Zfp335 deficiency. Collectively, our findings reveal that Zfp335 serves as a novel transcriptional factor upstream of TCF-1 in regulating CD8+ T cell memory.
    DOI:  https://doi.org/10.4049/jimmunol.2200026
  5. Nat Commun. 2022 Aug 05. 13(1): 4578
    Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers.
    Tom Van Nyen, Mélanie Planque, Lilian van Wagensveld, Joao A G Duarte, Esther A Zaal, Ali Talebi, Matteo Rossi, Pierre-René Körner, Lara Rizzotto, Stijn Moens, Wout De Wispelaere, Regina E M Baiden-Amissah, Gabe S Sonke, Hugo M Horlings, Guy Eelen, Emanuele Berardi, Johannes V Swinnen, Celia R Berkers, Peter Carmeliet, Diether Lambrechts, Ben Davidson, Reuven Agami, Sarah-Maria Fendt, Daniela Annibali, Frédéric Amant.
      Resistance to platinum-based chemotherapy represents a major clinical challenge for many tumors, including epithelial ovarian cancer. Patients often experience several response-relapse events, until tumors become resistant and life expectancy drops to 12-15 months. Despite improved knowledge of the molecular determinants of platinum resistance, the lack of clinical applicability limits exploitation of many potential targets, leaving patients with limited options. Serine biosynthesis has been linked to cancer growth and poor prognosis in various cancer types, however its role in platinum-resistant ovarian cancer is not known. Here, we show that a subgroup of resistant tumors decreases phosphoglycerate dehydrogenase (PHGDH) expression at relapse after platinum-based chemotherapy. Mechanistically, we observe that this phenomenon is accompanied by a specific oxidized nicotinamide adenine dinucleotide (NAD+) regenerating phenotype, which helps tumor cells in sustaining Poly (ADP-ribose) polymerase (PARP) activity under platinum treatment. Our findings reveal metabolic vulnerabilities with clinical implications for a subset of platinum resistant ovarian cancers.
    DOI:  https://doi.org/10.1038/s41467-022-32272-6
  6. Exp Hematol. 2022 Jul 28. pii: S0301-472X(22)00577-X. [Epub ahead of print]
    Mitochondrial Deep Dive into Hematopoietic Stem Cell Dormancy: Not Much Glycolysis but Plenty of Sluggish Lysosomes.
    Jiajing Qiu, Saghi Ghaffari.
      The discovery of hematopoietic stem cells (HSCs) heterogeneity have had major implications for investigations of hematopoietic stem cell disorders, clonal hematopoiesis and HSC aging. More recent studies of the heterogeneity of HSC organelles have begun to provide additional insights into the HSC behavior with far reaching ramifications for mechanistic understanding of aging of HSCs and stem cell-derived diseases. Mitochondrial heterogeneity has been explored to expose HSC subsets with distinct properties and functions. Here we review some of the recent advances in these lines of studies that challenged the classical view of glycolysis in HSCs and led to the identification of lysosomes as dynamic pivotal switch in controlling HSC quiescence vs. activation beyond their function in autophagy.
    DOI:  https://doi.org/10.1016/j.exphem.2022.07.299
  7. Front Immunol. 2022 ;13 969939
    Editorial: The role of immunometabolism in autoimmune mediated and autoinflammatory disorders.
    Valentina Pucino, Monica Guma.
      
    Keywords:  autoimmune disease; bioenergetic; cell metabolism; immunometabolism; inflammation
    DOI:  https://doi.org/10.3389/fimmu.2022.969939
  8. Biochem Pharmacol. 2022 Aug 01. pii: S0006-2952(22)00291-X. [Epub ahead of print] 115197
    mTOR Participates in the Formation, Maintenance, and Function of Memory CD8+T Cells Regulated by Glycometabolism.
    Xuepei Cai, Haokun Li, Manyi Wang, Edward Chu, Ning Wei, Jiayu Lin, Yun Hu, Jingtao Dai, Aijie Chen, Hua Zheng, Qianbing Zhang, Yuxia Zhong, Ruoshui Chang, Sha Wu, Yaomu Xiao, Chufeng Liu.
      Memory CD8+T cells participate in the fight against infection and tumorigenesis as well as in autoimmune disease progression because of their efficient and rapid immune response, long-term survival, and continuous differentiation. At each stage of their formation, maintenance, and function, the cell metabolism must be adjusted to match the functional requirements of the specific stage. Notably, enhanced glycolytic metabolism can generate sufficient levels of adenosine triphosphate (ATP) to form memory CD8+T cells, countering the view that glycolysis prevents the formation of memory CD8+T cells. This review focuses on how glycometabolism regulates memory CD8+T cells and highlights the key mechanisms through which the mammalian target of rapamycin (mTOR) signaling pathway affects memory CD8+T cell formation, maintenance, and function by regulating glycometabolism. In addition, different subpopulations of memory CD8+T cells exhibit different metabolic flexibility during their formation, survival, and functional stages, during which the energy metabolism may be critical. These findings which may explain why enhanced glycolytic metabolism can give rise to memory CD8+T cells. Modulating the metabolism of memory CD8+T cells to influence specific cell fates may be useful for disease treatment.
    Keywords:  Glycolysis; Glycometabolism; Memory CD8(+)T cell; mTOR
    DOI:  https://doi.org/10.1016/j.bcp.2022.115197
  9. Free Radic Biol Med. 2022 Jul 30. pii: S0891-5849(22)00496-8. [Epub ahead of print]
    Nrf2 as a regulator of mitochondrial function: Energy metabolism and beyond.
    Noemí Esteras, Andrey Y Abramov.
      Mitochondria are unique and essential organelles that mediate many vital cellular processes including energy metabolism and cell death. The transcription factor Nrf2 (NF-E2 p45-related factor 2) has emerged in the last few years as an important modulator of multiple aspects of mitochondrial function. Well-known for controlling cellular redox homeostasis, the cytoprotective effects of Nrf2 extend beyond its ability to regulate a diverse network of antioxidant and detoxification enzymes. Here, we review the role of Nrf2 in the regulation of mitochondrial function and structure. We focus on Nrf2 involvement in promoting mitochondrial quality control and regulation of basic aspects of mitochondrial function, including energy production, reactive oxygen species generation, calcium signalling, and cell death induction. Given the importance of mitochondria in the development of multiple diseases, these findings reinforce the pharmacological activation of Nrf2 as an attractive strategy to counteract mitochondrial dysfunction.
    Keywords:  Calcium; Dynamics; Energy; Fission; Fusion; Mitochondria; Mitochondrial biogenesis; Mitophagy; Nrf2; ROS; mPTP
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.07.013
  10. Front Nutr. 2022 ;9 914457
    Vitamin A, systemic T-cells, and the eye: Focus on degenerative retinal disease.
    Arun J Thirunavukarasu, A Catharine Ross, Rose M Gilbert.
      The first discovered vitamin, vitamin A, exists in a range of forms, primarily retinoids and provitamin carotenoids. The bioactive forms of vitamin A, retinol and retinoic acid, have many critical functions in body systems including the eye and immune system. Vitamin A deficiency is associated with dysfunctional immunity, and presents clinically as a characteristic ocular syndrome, xerophthalmia. The immune functions of vitamin A extend to the gut, where microbiome interactions and nutritional retinoids and carotenoids contribute to the balance of T cell differentiation, thereby determining immune status and contributing to inflammatory disease around the whole body. In the eye, degenerative conditions affecting the retina and uvea are influenced by vitamin A. Stargardt's disease (STGD1; MIM 248200) is characterised by bisretinoid deposits such as lipofuscin, produced by retinal photoreceptors as they use and recycle a vitamin A-derived chromophore. Age-related macular degeneration features comparable retinal deposits, such as drusen featuring lipofuscin accumulation; and is characterised by parainflammatory processes. We hypothesise that local parainflammatory processes secondary to lipofuscin deposition in the retina are mediated by T cells interacting with dietary vitamin A derivatives and the gut microbiome, and outline the current evidence for this. No cures exist for Stargardt's or age-related macular degeneration, but many vitamin A-based therapeutic approaches have been or are being trialled. The relationship between vitamin A's functions in systemic immunology and the eye could be further exploited, and further research may seek to leverage the interactions of the gut-eye immunological axis.
    Keywords:  Stargardt’s disease; T cell; age - related macular degeneration; carotenoids; gut microbiome; retina; retinoids; vitamin A
    DOI:  https://doi.org/10.3389/fnut.2022.914457
  11. Clin Transl Med. 2022 Aug;12(8): e999
    Iron controls T helper cell pathogenicity by promoting glucose metabolism in autoimmune myopathy.
    Yimei Lai, Siyuan Zhao, Binfeng Chen, Yuefang Huang, Chaohuan Guo, Mengyuan Li, Baokui Ye, Shuyi Wang, Hui Zhang, Niansheng Yang.
      BACKGROUND: T helper cells in patients with autoimmune disease of idiopathic inflammatory myopathies (IIM) are characterized with the proinflammatory phenotypes. The underlying mechanisms remain unknown.METHODS: RNA sequencing was performed for differential expression genes. Gene expression in CD4+ T-cells was confirmed by quantitative real-time PCR. CD4+ T-cells from IIM patients or healthy controls were evaluated for metabolic activities by Seahorse assay. Glucose uptake, T-cell proliferation and differentiation were evaluated and measured by flow cytometry. Human CD4+ T-cells treated with iron chelators or Pfkfb4 siRNA were measured for glucose metabolism, proliferation and differentiation. Signalling pathway activation was evaluated by western blot and flow cytometry. Mouse model of experimental autoimmune myositis (EAM) were induced and treated with iron chelator or rapamycin. CD4+ T-cell differentiation and muscle inflammation in the EAM mice were evaluated.
    RESULTS: RNA-sequencing analysis revealed that iron was involved with glucose metabolism and CD4+ T-cell differentiation. IIM patient-derived CD4+ T-cells showed enhanced glycolysis and mitochondrial respiration, which was inhibited by iron chelation. CD4+ T-cells from patients with IIM was proinflammatory and iron chelation suppressed the differentiation of interferon gamma (IFNγ)- and interleukin (IL)-17A-producing CD4+ T-cells, which resulted in an increased percentage of regulatory T (Treg) cells. Mechanistically, iron promoted glucose metabolism by an upregulation of PFKFB4 through AKT-mTOR signalling pathway. Notably, the knockdown of Pfkfb4 decreased glucose influx and thus suppressed the differentiation of IFNγ- and IL-17A-producing CD4+ T-cells. In vivo, iron chelation inhibited mTOR signalling pathway and reduced PFKFB4 expression in CD4+ T-cells, resulting in reduced proinflammatory IFNγ- and IL-17A-producing CD4+ T-cells and increased Foxp3+ Treg cells, leading to ameliorated muscle inflammation.
    CONCLUSIONS: Iron directs CD4+ T-cells into a proinflammatory phenotype by enhancing glucose metabolism. Therapeutic targeting of iron metabolism should have the potential to normalize glucose metabolism in CD4+ T-cells and reverse their proinflammatory phenotype in IIM.
    Keywords:  PFKFB4; T helper cells; autoimmune myopathy; glucose metabolism; iron
    DOI:  https://doi.org/10.1002/ctm2.999
  12. Proc Natl Acad Sci U S A. 2022 Aug 09. 119(32): e2114758119
    Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation.
    Desi C Alexander, Tanya Corman, Mariel Mendoza, Andrew Glass, Tal Belity, Ranran Wu, Rianne R Campbell, Joseph Han, Ashley A Keiser, Jeffrey Winkler, Marcelo A Wood, Thomas Kim, Benjamin A Garcia, Hagit Cohen, Philipp Mews, Gabor Egervari, Shelley L Berger.
      Histone acetylation is a key component in the consolidation of long-term fear memories. Histone acetylation is fueled by acetyl-coenzyme A (acetyl-CoA), and recently, nuclear-localized metabolic enzymes that produce this metabolite have emerged as direct and local regulators of chromatin. In particular, acetyl-CoA synthetase 2 (ACSS2) mediates histone acetylation in the mouse hippocampus. However, whether ACSS2 regulates long-term fear memory remains to be determined. Here, we show that Acss2 knockout is well tolerated in mice, yet the Acss2-null mouse exhibits reduced acquisition of long-term fear memory. Loss of Acss2 leads to reductions in both histone acetylation and expression of critical learning and memory-related genes in the dorsal hippocampus, specifically following fear conditioning. Furthermore, systemic administration of blood-brain barrier-permeable Acss2 inhibitors during the consolidation window reduces fear-memory formation in mice and rats and reduces anxiety in a predator-scent stress paradigm. Our findings suggest that nuclear acetyl-CoA metabolism via ACSS2 plays a critical, previously unappreciated, role in the formation of fear memories.
    Keywords:  epigenetics; fear conditioning; histone acetylation; learning and memory; mass spectrometry
    DOI:  https://doi.org/10.1073/pnas.2114758119
  13. Front Oncol. 2022 ;12 931104
    A novel strategy to fuel cancer immunotherapy: targeting glucose metabolism to remodel the tumor microenvironment.
    Xu Liu, Yujie Zhao, Xi Wu, Zhihui Liu, Xiaowei Liu.
      The promising results of immunotherapy in tumors have changed the current treatment modality for cancer. However, the remarkable responses are limited to a minority of patients, which is due to immune suppression in the tumor microenvironment (TME). These include the pre-exists of suppressive immune cells, physical barriers to immune infiltration, antigen and antigen presentation deficiency, and expression of inhibitory immune checkpoint molecules. Recently, increasing evidence reveal that tumor metabolism, especially abnormal glucose metabolism of tumors, plays an essential role in tumor immune escape and is a potential target to combine with immunotherapy. By glucose uptake, tumor cells alter their metabolism to facilitate unregulated cellular proliferation and survival and regulate the expression of inhibitory immune checkpoint molecules. Meanwhile, glucose metabolism also regulates the activation, differentiation, and functions of immunocytes. In addition, tumor mainly utilizes glycolysis for energy generation and cellular proliferation, which cause the TME to deplete nutrients for infiltrating immune cells such as T cells and produce immunosuppressive metabolites. Thus, therapeutics that target glucose metabolism, such as inhibiting glycolytic activity, alleviating hypoxia, and targeting lactate, have shown promise as combination therapies for different types of cancer. In this review, we summarized the functions of glucose metabolism in the tumor cells, immune cells, and tumor microenvironment, as well as strategies to target glucose metabolism in combination with immune checkpoint blockade for tumor therapy.
    Keywords:  aerobic glycolysis; glucose metabolism; immune checkpoint inhibitors; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.931104
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