bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022–11–20
twelve papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. CD8+ T cell metabolic rewiring defined by scRNA-seq identifies a critical role of ASNS expression dynamics in T cell differentiation.
  2. Multiomics analysis couples mRNA turnover and translational control of glutamine metabolism to the differentiation of the activated CD4+ T cell.
  3. mTOR regulates T cell exhaustion and PD-1 targeted immunotherapy response during chronic viral infection.
  4. Chronic type I interferon signaling promotes lipid-peroxidation-driven terminal CD8+ T cell exhaustion and curtails anti-PD-1 efficacy.
  5. Suppression of CD8+ T cells by the metabolite itaconate.
  6. How slimming regulatory T cells limit atherosclerosis: Mechanistic insights into T cell lipid metabolism.
  7. RNA Metabolism in T Lymphocytes.
  8. Aging beyond menopause selectively decreases CD8+ T cell numbers but enhances cytotoxic activity in the human endometrium.
  9. Tumour-derived D-2HG blocks T cell cytotoxicity.
  10. OXPHOS promotes apoptotic resistance and cellular persistence in TH17 cells in the periphery and tumor microenvironment.
  11. The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity.
  12. Adenosine signaling in T-cell activation favors development of IL-17 positive cells with suppressive properties.
  1. Cell Rep. 2022 Nov 15. pii: S2211-1247(22)01510-8. [Epub ahead of print]41(7): 111639
    CD8+ T cell metabolic rewiring defined by scRNA-seq identifies a critical role of ASNS expression dynamics in T cell differentiation.
    Juan Fernández-García, Fabien Franco, Sweta Parik, Patricia Altea-Manzano, Antonino Alejandro Pane, Dorien Broekaert, Joke van Elsen, Ines Vermeire, Tessa Schalley, Mélanie Planque, Thomas van Brussel, Rogier Schepers, Elodie Modave, Tobias K Karakach, Peter Carmeliet, Diether Lambrechts, Ping-Chih Ho, Sarah-Maria Fendt.
      T cells dynamically rewire their metabolism during an immune response. We applied single-cell RNA sequencing to CD8+ T cells activated and differentiated in vitro in physiological medium to resolve these metabolic dynamics. We identify a differential time-dependent reliance of activating T cells on the synthesis versus uptake of various non-essential amino acids, which we corroborate with functional assays. We also identify metabolic genes that potentially dictate the outcome of T cell differentiation, by ranking them based on their expression dynamics. Among them, we find asparagine synthetase (Asns), whose expression peaks for effector T cells and decays toward memory formation. Disrupting these expression dynamics by ASNS overexpression promotes an effector phenotype, enhancing the anti-tumor response of adoptively transferred CD8+ T cells in a mouse melanoma model. We thus provide a resource of dynamic expression changes during CD8+ T cell activation and differentiation, and identify ASNS expression dynamics as a modulator of CD8+ T cell differentiation.
    Keywords:  ASNS; CD8(+) T cells; CP: Immunology; T-cell activation; T-cell differentiation; asparagine; dynamics; immunology; metabolism; physiological media; scRNA-seq
    DOI:  https://doi.org/10.1016/j.celrep.2022.111639
  2. Sci Rep. 2022 Nov 16. 12(1): 19657
    Multiomics analysis couples mRNA turnover and translational control of glutamine metabolism to the differentiation of the activated CD4+ T cell.
    Louise S Matheson, Georg Petkau, Beatriz Sáenz-Narciso, Vanessa D'Angeli, Jessica McHugh, Rebecca Newman, Haydn Munford, James West, Krishnendu Chakraborty, Jennie Roberts, Sebastian Łukasiak, Manuel D Díaz-Muñoz, Sarah E Bell, Sarah Dimeloe, Martin Turner.
      The ZFP36 family of RNA-binding proteins acts post-transcriptionally to repress translation and promote RNA decay. Studies of genes and pathways regulated by the ZFP36 family in CD4+ T cells have focussed largely on cytokines, but their impact on metabolic reprogramming and differentiation is unclear. Using CD4+ T cells lacking Zfp36 and Zfp36l1, we combined the quantification of mRNA transcription, stability, abundance and translation with crosslinking immunoprecipitation and metabolic profiling to determine how they regulate T cell metabolism and differentiation. Our results suggest that ZFP36 and ZFP36L1 act directly to limit the expression of genes driving anabolic processes by two distinct routes: by targeting transcription factors and by targeting transcripts encoding rate-limiting enzymes. These enzymes span numerous metabolic pathways including glycolysis, one-carbon metabolism and glutaminolysis. Direct binding and repression of transcripts encoding glutamine transporter SLC38A2 correlated with increased cellular glutamine content in ZFP36/ZFP36L1-deficient T cells. Increased conversion of glutamine to α-ketoglutarate in these cells was consistent with direct binding of ZFP36/ZFP36L1 to Gls (encoding glutaminase) and Glud1 (encoding glutamate dehydrogenase). We propose that ZFP36 and ZFP36L1 as well as glutamine and α-ketoglutarate are limiting factors for the acquisition of the cytotoxic CD4+ T cell fate. Our data implicate ZFP36 and ZFP36L1 in limiting glutamine anaplerosis and differentiation of activated CD4+ T cells, likely mediated by direct binding to transcripts of critical genes that drive these processes.
    DOI:  https://doi.org/10.1038/s41598-022-24132-6
  3. J Clin Invest. 2022 Nov 15. pii: e160025. [Epub ahead of print]
    mTOR regulates T cell exhaustion and PD-1 targeted immunotherapy response during chronic viral infection.
    Satomi Ando, Charles Perkins, Yamato Sajiki, Chase Chastain, Rajesh M Valanparambil, Andreas Wieland, William H Hudson, Masao Hashimoto, Suresh S Ramalingam, Gordon J Freeman, Rafi Ahmed, Koichi Araki.
      T cell exhaustion is a state of T cell dysfunction associated with expression of programmed death 1 (PD-1). Exhausted CD8 T cells are maintained by self-renewing stem-like T (TSL) cells that provide differentiated TIM3+ cells, a part of which possesses effector-like properties. PD-1-targeted therapies enhance T cell response by promoting differentiation of TSL cells toward TIM3+ cells, but the role of mTOR during T cell exhaustion remains elusive. Here, we show that mTOR inhibition has distinct outcomes during the beginning of and after the establishment of chronic viral infection. Blocking mTOR during the T cell expansion phase enhanced the T cell response by accumulating TSL cells, leading to improved efficacy of PD-1 immunotherapy. Whereas, after exhaustion progressed, mTOR inhibition caused immunosuppression characterized by decreased TIM3+ cells and increased viral load with minimal changes in TSL cells. Mechanistically, a cell-intrinsic mTOR signal was vital for differentiation of TSL cells into the TIM3+ state in the early and late phases of chronic infection as well as during PD-1 immunotherapy. Thus, PD-1 blockade worked after cessation of mTOR inhibition but simultaneous treatment failed to induce functional TIM3+ cells, reducing efficacy of PD-1 immunotherapy. Our data demonstrate that mTOR regulates T cell exhaustion and have important implications for combination cancer therapies with PD-1 blockade.
    Keywords:  Adaptive immunity; Immunology; Immunotherapy; Infectious disease; T cells
    DOI:  https://doi.org/10.1172/JCI160025
  4. Cell Rep. 2022 Nov 15. pii: S2211-1247(22)01518-2. [Epub ahead of print]41(7): 111647
    Chronic type I interferon signaling promotes lipid-peroxidation-driven terminal CD8+ T cell exhaustion and curtails anti-PD-1 efficacy.
    Weixin Chen, Jia Ming Nickolas Teo, Siu Wah Yau, Melody Yee-Man Wong, Chun-Nam Lok, Chi-Ming Che, Asif Javed, Yuanhua Huang, Stephanie Ma, Guang Sheng Ling.
      Identifying signals that govern the differentiation of tumor-infiltrating CD8+ T cells (CD8+ TILs) toward exhaustion can improve current therapeutic approaches for cancer. Here, we show that type I interferons (IFN-Is) act as environmental cues, enhancing terminal CD8+ T cell exhaustion in tumors. We find enrichment of IFN-I-stimulated genes (ISGs) within exhausted CD8+ T cells (Tex cells) in patients across various cancer types, with heightened ISG levels correlating with poor response to immune checkpoint blockade (ICB) therapy. In preclinical models, CD8+ TILs devoid of IFN-I signaling develop less exhaustion features, provide better tumor control, and show greater response to ICB-mediated rejuvenation. Mechanistically, chronic IFN-I stimulation perturbs lipid metabolism and redox balance in Tex cells, leading to aberrant lipid accumulation and elevated oxidative stress. Collectively, these defects promote lipid peroxidation, which potentiates metabolic and functional exhaustion of Tex cells. Thus, cell-intrinsic IFN-I signaling regulates the extent of CD8+ TIL exhaustion and has important implications for immunotherapy.
    Keywords:  CD8(+) T cell exhaustion; CP: Immunology; anti-PD-1 therapy resistance; chronic IFN-I signaling; dysregulated lipid metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2022.111647
  5. Nat Metab. 2022 Nov 14.
    Suppression of CD8+ T cells by the metabolite itaconate.
      
    DOI:  https://doi.org/10.1038/s42255-022-00694-7
  6. Atherosclerosis. 2022 Nov 10. pii: S0021-9150(22)01498-8. [Epub ahead of print]
    How slimming regulatory T cells limit atherosclerosis: Mechanistic insights into T cell lipid metabolism.
    Emiel P C van der Vorst, Yvonne Döring.
      
    Keywords:  Angiopoietin-like 3; Atherosclerosis; Lipid metabolism; Regulatory T cells; Therapy
    DOI:  https://doi.org/10.1016/j.atherosclerosis.2022.11.002
  7. Immune Netw. 2022 Oct;22(5): e39
    RNA Metabolism in T Lymphocytes.
    Jin Ouk Choi, Jeong Hyeon Ham, Soo Seok Hwang.
      RNA metabolism plays a central role in regulating of T cell-mediated immunity. RNA processing, modifications, and regulations of RNA decay influence the tight and rapid regulation of gene expression during T cell phase transition. Thymic selection, quiescence maintenance, activation, differentiation, and effector functions of T cells are dependent on selective RNA modulations. Recent technical improvements have unveiled the complex crosstalk between RNAs and T cells. Moreover, resting T cells contain large amounts of untranslated mRNAs, implying that the regulation of RNA metabolism might be a key step in controlling gene expression. Considering the immunological significance of T cells for disease treatment, an understanding of RNA metabolism in T cells could provide new directions in harnessing T cells for therapeutic implications.
    Keywords:  Cellular; Immunity; RNA; RNA metabolism; T-lymphocytes
    DOI:  https://doi.org/10.4110/in.2022.22.e39
  8. Immun Ageing. 2022 Nov 12. 19(1): 55
    Aging beyond menopause selectively decreases CD8+ T cell numbers but enhances cytotoxic activity in the human endometrium.
    Zheng Shen, Mickey V Patel, Marta Rodriguez-Garcia, Charles R Wira.
       BACKGROUND: Regulation of endometrial (EM) CD8+ T cells, which provide protection through cell-mediated cytotoxicity, is essential for successful reproduction, and protection against sexually transmitted infections and potential tumors. We have previously demonstrated that EM CD8+ T cell cytotoxicity is suppressed directly and indirectly by sex hormones and enhanced after menopause. What remains unclear is whether CD8+ T cell protection and the contribution of tissue-resident (CD103+) and non-resident (CD103-) T cell populations in the EM change as women age following menopause.
    RESULTS: Using hysterectomy EM tissues, we found that EM CD8+ T cell numbers declined significantly in the years following menopause. Despite an overall decline in CD8+ T cells, cytotoxic activity per cell for both CD103- and CD103 + CD8+ T cells increased with age. Investigation of the underlying mechanisms responsible for cytotoxicity indicated that the percentage of total granzyme A and granzyme B positive CD8+ T cells, but not perforin, increased significantly after menopause and remained high and constant as women aged. Additionally, baseline TNFα production by EM CD8+ T cells increased significantly in the years following menopause, and estradiol suppressed TNFα secretion. Moreover, in response to PMA activation, TNFα and IFNγ were significantly up-regulated, and CD103-CD8+ T cells up-regulation of TNFα, IFNγ and IL-6 increased as women aged.
    CONCLUSIONS: Understanding the underlying factors involved in regulating cell-mediated protection of the EM by CD8+ T cells will contribute to the foundation of information essential for developing therapeutic tools to protect women against gynecological cancers and infections as they age.
    Keywords:  Aging; CD8+ T cells; Cytotoxic activity; Endometrium; Menopause
    DOI:  https://doi.org/10.1186/s12979-022-00312-w
  9. Nat Rev Cancer. 2022 Nov 14.
    Tumour-derived D-2HG blocks T cell cytotoxicity.
    Joseph Willson.
      
    DOI:  https://doi.org/10.1038/s41568-022-00534-6
  10. Sci Immunol. 2022 Nov 25. 7(77): eabm8182
    OXPHOS promotes apoptotic resistance and cellular persistence in TH17 cells in the periphery and tumor microenvironment.
    Hanna S Hong, Nneka E Mbah, Mengrou Shan, Kristen Loesel, Lin Lin, Peter Sajjakulnukit, Luis O Correa, Anthony Andren, Jason Lin, Atsushi Hayashi, Brian Magnuson, Judy Chen, Zhaoheng Li, Yuying Xie, Li Zhang, Daniel R Goldstein, Shannon A Carty, Yu Leo Lei, Anthony W Opipari, Rafael J Argüello, Ilona Kryczek, Nobuhiko Kamada, Weiping Zou, Luigi Franchi, Costas A Lyssiotis.
      T cell proliferation and cytokine production are bioenergetically and biosynthetically costly. The inability to meet these metabolic demands results in altered differentiation, accompanied by impaired effector function, and attrition of the immune response. Interleukin-17-producing CD4 T cells (TH17s) are mediators of host defense, autoimmunity, and antitumor immunity in the setting of adoptive T cell therapy. TH17s are long-lived cells that require mitochondrial oxidative phosphorylation (OXPHOS) for effector function in vivo. Considering that TH17s polarized under standardized culture conditions are predominately glycolytic, little is known about how OXPHOS regulates TH17 processes, such as their ability to persist and thus contribute to protracted immune responses. Here, we modified standardized culture medium and identified a culture system that reliably induces OXPHOS dependence in TH17s. We found that TH17s cultured under OXPHOS conditions metabolically resembled their in vivo counterparts, whereas glycolytic cultures were dissimilar. OXPHOS TH17s exhibited increased mitochondrial fitness, glutamine anaplerosis, and an antiapoptotic phenotype marked by high BCL-XL and low BIM. Limited mitophagy, mediated by mitochondrial fusion regulator OPA-1, was critical to apoptotic resistance in OXPHOS TH17s. By contrast, glycolytic TH17s exhibited more mitophagy and an imbalance in BCL-XL to BIM, thereby priming them for apoptosis. In addition, through adoptive transfer experiments, we demonstrated that OXPHOS protected TH17s from apoptosis while enhancing their persistence in the periphery and tumor microenvironment in a murine model of melanoma. Together, our work demonstrates how metabolism regulates TH17 cell fate and highlights the potential for therapies that target OXPHOS in TH17-driven diseases.
    DOI:  https://doi.org/10.1126/sciimmunol.abm8182
  11. Immunity. 2022 Nov 01. pii: S1074-7613(22)00561-1. [Epub ahead of print]
    The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity.
    Sabelo Lukhele, Diala Abd Rabbo, Mengdi Guo, Jian Shen, Heidi J Elsaesser, Rene Quevedo, Madeleine Carew, Ramy Gadalla, Laura M Snell, Lawanya Mahesh, M Teresa Ciudad, Bryan E Snow, Annick You-Ten, Jillian Haight, Andrew Wakeham, Pamela S Ohashi, Tak W Mak, Weiguo Cui, Tracy L McGaha, David G Brooks.
      Type I and II interferons (IFNs) stimulate pro-inflammatory programs that are critical for immune activation, but also induce immune-suppressive feedback circuits that impede control of cancer growth. Here, we sought to determine how these opposing programs are differentially induced. We demonstrated that the transcription factor interferon regulatory factor 2 (IRF2) was expressed by many immune cells in the tumor in response to sustained IFN signaling. CD8+ T cell-specific deletion of IRF2 prevented acquisition of the T cell exhaustion program within the tumor and instead enabled sustained effector functions that promoted long-term tumor control and increased responsiveness to immune checkpoint and adoptive cell therapies. The long-term tumor control by IRF2-deficient CD8+ T cells required continuous integration of both IFN-I and IFN-II signals. Thus, IRF2 is a foundational feedback molecule that redirects IFN signals to suppress T cell responses and represents a potential target to enhance cancer control.
    Keywords:  CD8(+) T cells; CyTOF; IRF2; T cell exhaustion; adoptive cell transfer; cancer; immunotherapy; interferon gamma; interferon regulatory factor 2; type I interferon
    DOI:  https://doi.org/10.1016/j.immuni.2022.10.020
  12. Immunology. 2022 Nov 14.
    Adenosine signaling in T-cell activation favors development of IL-17 positive cells with suppressive properties.
    Lisa Leikeim, Hui Li, Liying An, Carsten Sticht, Bernhard K Krämer, Benito Yard, Jan Leipe, Anna-Isabelle Kälsch.
       BACKGROUND: Evidence suggests that the anti-inflammatory nucleoside adenosine can shape immune responses by shifting the regulatory (Treg)/helper (Th17) T-cell balance in favor of Tregs. Since this observation is based on in vivo and in vitro studies mostly confined to murine models, we comprehensively analyzed effects of adenosine on human T-cells.
    METHODS: Proliferation, phenotype and cytokine production of stimulated T-cells were assessed by flow cytometry, multiplex assay and ELISA, gene expression profiling was determined by microarray.
    RESULTS: We found that the pan-adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA) skews human CD3+ T-cell responses towards non-inflammatory Th17 cells. Addition of NECA during T-cell activation increased the development of IL-17+ cells with a CD4+ RORγt+ phenotype and enhanced CD161 and CD196 surface expression. Remarkably, these Th17 cells displayed non-inflammatory cytokine and gene expression profiles including reduced Th1/Th17 transdifferentiation, a stem cell-like molecular signature and induced surface expression of the adenosine-producing ectoenzymes CD39 and CD73. Thus, T-cells cultured under Th17-inducing conditions together with NECA were capable of suppressing responder T-cells. Finally, genome-wide gene expression profiling revealed metabolic quiescence previously associated with non-pathogenic Th17 cells in response to adenosine signaling.
    CONCLUSION: Our data suggest that adenosine induces non-inflammatory Th17 cells in human T-cell differentiation, potentially through regulation of metabolic pathways.
    Keywords:  Regulation/suppression; Th17; cell differentiation; human; inflammation
    DOI:  https://doi.org/10.1111/imm.13608
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