bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021‒02‒07
fourteen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research


  1. Nat Commun. 2021 Feb 05. 12(1): 832
    Yang R, Sun L, Li CF, Wang YH, Yao J, Li H, Yan M, Chang WC, Hsu JM, Cha JH, Hsu JL, Chou CW, Sun X, Deng Y, Chou CK, Yu D, Hung MC.
      The two T cell inhibitory receptors PD-1 and TIM-3 are co-expressed during exhausted T cell differentiation, and recent evidence suggests that their crosstalk regulates T cell exhaustion and immunotherapy efficacy; however, the molecular mechanism is unclear. Here we show that PD-1 contributes to the persistence of PD-1+TIM-3+ T cells by binding to the TIM-3 ligand galectin-9 (Gal-9) and attenuates Gal-9/TIM-3-induced cell death. Anti-Gal-9 therapy selectively expands intratumoral TIM-3+ cytotoxic CD8 T cells and immunosuppressive regulatory T cells (Treg cells). The combination of anti-Gal-9 and an agonistic antibody to the co-stimulatory receptor GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) that depletes Treg cells induces synergistic antitumor activity. Gal-9 expression and secretion are promoted by interferon β and γ, and high Gal-9 expression correlates with poor prognosis in multiple human cancers. Our work uncovers a function for PD-1 in exhausted T cell survival and suggests Gal-9 as a promising target for immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-021-21099-2
  2. J Immunol. 2021 Feb 05. pii: ji2000672. [Epub ahead of print]
    Kushnareva Y, Mathews IT, Andreyev AY, Altay G, Lindestam Arlehamn CS, Pandurangan V, Nilsson R, Jain M, Sette A, Peters B, Sharma S.
      CCR6+CXCR3+CCR4-CD4+ memory T cells, termed Th1*, are important for long-term immunity to Mycobacterium tuberculosis and the pathogenesis of autoimmune diseases. Th1* cells express a unique set of lineage-specific transcription factors characteristic of both Th1 and Th17 cells and display distinct gene expression profiles compared with other CD4+ T cell subsets. To examine molecules and signaling pathways important for the effector function of Th1* cells, we performed loss-of-function screening of genes selectively enriched in the Th1* subset. The genetic screen yielded candidates whose depletion significantly impaired TCR-induced IFN-γ production. These included genes previously linked to IFN-γ or M. tuberculosis susceptibility and novel candidates, such as ISOC1, encoding a metabolic enzyme of unknown function in mammalian cells. ISOC1-depleted T cells, which produced less IFN-γ and IL-17, displayed defects in oxidative phosphorylation and glycolysis and impairment of pyrimidine metabolic pathway. Supplementation with extracellular pyrimidines rescued both bioenergetics and IFN-γ production in ISOC1-deficient T cells, indicating that pyrimidine metabolism is a key driver of effector functions in CD4+ T cells and Th1* cells. Results provide new insights into the immune-stimulatory function of ISOC1 as well as the particular metabolic requirements of human memory T cells, providing a novel resource for understanding long-term T cell-driven responses.
    DOI:  https://doi.org/10.4049/jimmunol.2000672
  3. Cell Rep. 2021 Feb 02. pii: S2211-1247(21)00029-2. [Epub ahead of print]34(5): 108716
    Fahl SP, Contreras AV, Verma A, Qiu X, Harly C, Radtke F, Zúñiga-Pflücker JC, Murre C, Xue HH, Sen JM, Wiest DL.
      TCF1 plays a critical role in T lineage commitment and the development of αβ lineage T cells, but its role in γδ T cell development remains poorly understood. Here, we reveal a regulatory axis where T cell receptor (TCR) signaling controls TCF1 expression through an E-protein-bound regulatory element in the Tcf7 locus, and this axis regulates both γδ T lineage commitment and effector fate. Indeed, the level of TCF1 expression plays an important role in setting the threshold for γδ T lineage commitment and modulates the ability of TCR signaling to influence effector fate adoption by γδ T lineage progenitors. This finding provides mechanistic insight into how TCR-mediated repression of E proteins promotes the development of γδ T cells and their adoption of the interleukin (IL)-17-producing effector fate. IL-17-producing γδ T cells have been implicated in cancer progression and in the pathogenesis of psoriasis and multiple sclerosis.
    Keywords:  E proteins; T cell receptor (TCR); TCF1; TCR signaling; development; interleukin-17; γδ T cell
    DOI:  https://doi.org/10.1016/j.celrep.2021.108716
  4. Aging Cell. 2021 Feb 01. e13316
    Zhou D, Borsa M, Simon AK.
      The ageing of the global population brings about unprecedented challenges. Chronic age-related diseases in an increasing number of people represent an enormous burden for health and social care. The immune system deteriorates during ageing and contributes to many of these age-associated diseases due to its pivotal role in pathogen clearance, tissue homeostasis and maintenance. Moreover, in order to develop treatments for COVID-19, we urgently need to acquire more knowledge about the aged immune system, as older adults are disproportionally and more severely affected. Changes with age lead to impaired responses to infections, malignancies and vaccination, and are accompanied by chronic, low-degree inflammation, which together is termed immunosenescence. However, the molecular and cellular mechanisms that underlie immunosenescence, termed immune cell senescence, are mostly unknown. Cellular senescence, characterised by an irreversible cell cycle arrest, is thought to be the cause of tissue and organismal ageing. Thus, better understanding of cellular senescence in immune populations at single-cell level may provide us with insight into how immune cell senescence develops over the life time of an individual. In this review, we will briefly introduce the phenotypic characterisation of aged innate and adaptive immune cells, which also contributes to overall immunosenescence, including subsets and function. Next, we will focus on the different hallmarks of cellular senescence and cellular ageing, and the detection techniques most suitable for immune cells. Applying these techniques will deepen our understanding of immune cell senescence and to discover potential druggable pathways, which can be modulated to reverse immune ageing.
    Keywords:  ageing markers; immunosenescence; methods
    DOI:  https://doi.org/10.1111/acel.13316
  5. Immunol Cell Biol. 2021 Feb 06.
    Kwong CJ, Selck C, Tahija K, McAnaney LJ, Le DV, Kay TW, Thomas HE, Krishnamurthy B.
      Although immune interventions have shown great promise in type 1 diabetes clinical trials, none is yet in routine clinical use or able to achieve insulin independence in patients. In addition to this, the principles of type 1 diabetes treatment remain essentially unchanged since the isolation of insulin, almost a century ago. Type 1 diabetes is characterised by insulin deficiency due to destruction of insulin-producing beta cells mediated by autoreactive T cells. Therapies that target beta-cell antigen specific T cells are needed to prevent type 1 diabetes. CD8+ T-cell exhaustion is an emerging area of research in chronic infection, cancer immunotherapy, and more recently, autoimmunity. Recent data suggest that exhausted T cell populations are associated with improved markers of type 1 diabetes. T-cell exhaustion is both characterised and mediated by inhibitory receptors. This review aims to identify which inhibitory receptors may prove useful to induce T-cell exhaustion to treat type 1 diabetes and identify limitations and gaps in the current literature.
    Keywords:  CD8+ T cells; PD-1; T-cell exhaustion; Type 1 diabetes
    DOI:  https://doi.org/10.1111/imcb.12444
  6. Nat Commun. 2021 01 27. 12(1): 610
    Norin U, Rintisch C, Meng L, Forster F, Ekman D, Tuncel J, Klocke K, Bäcklund J, Yang M, Bonner MY, Lahore GF, James J, Shchetynsky K, Bergquist M, Gjertsson I, Hubner N, Bäckdahl L, Holmdahl R.
      The introduction of the CTLA-4 recombinant fusion protein has demonstrated therapeutic effects by selectively modulating T-cell activation in rheumatoid arthritis. Here we show, using a forward genetic approach, that a mutation in the SH3gl1 gene encoding the endocytic protein Endophilin A2 is associated with the development of arthritis in rodents. Defective expression of SH3gl1 affects T cell effector functions and alters the activation threshold of autoreactive T cells, thereby leading to complete protection from chronic autoimmune inflammatory disease in both mice and rats. We further show that SH3GL1 regulates human T cell signaling and T cell receptor internalization, and its expression is upregulated in rheumatoid arthritis patients. Collectively our data identify SH3GL1 as a key regulator of T cell activation, and as a potential target for treatment of autoimmune diseases.
    DOI:  https://doi.org/10.1038/s41467-020-20586-2
  7. Exp Hematol. 2021 Jan 27. pii: S0301-472X(21)00031-X. [Epub ahead of print]
    Filippi MD.
      Hematopoietic stem cells are characterized by their ability to produce all cells of the blood and immune system and have been used for transplantation for decades. Although the regenerative potential of HSCs is high, their self-renewal potential is limited. HSC functions are inversely correlated with their divisional history. Recent advances in our understanding of the regulation of HSC through cell division suggest that HSCs may never replicate into identical self, but rather replicate into progeny that gradually loose functionality at each round of division. HSCs division is accompanied by major transcriptional and metabolic changes. This perspective discusses the possibility that mitochondrial metabolism confers HSC division memory and programs HSCs for extinction.
    DOI:  https://doi.org/10.1016/j.exphem.2021.01.006
  8. Front Immunol. 2020 ;11 604591
    Rodriguez IJ, Lalinde Ruiz N, Llano León M, Martínez Enríquez L, Montilla Velásquez MDP, Ortiz Aguirre JP, Rodríguez Bohórquez OM, Velandia Vargas EA, Hernández ED, Parra López CA.
      Background: Aging is accompanied by alterations in immune response which leads to increased susceptibility to infectious diseases, cancer, autoimmunity, and inflammatory disorders. This decline in immune function is termed as immunosenescence; however, the mechanisms are not fully elucidated. Experimental approaches of adaptive immunity, particularly for T cells, have been the main focus of immunosenescence research. This systematic review evaluates and discusses T cell markers implicated in immunosenescence.Objective: To determine the best flow cytometry markers of circulating T cells associated with immunosenescence.
    Methods: We systematically queried PubMed, MEDLINE, EBSCO, and BVS databases for original articles focused on two age groups of healthy humans: 18-44 (young adults) and >60 (older adults) years. In accordance with the Cochrane methodology, we synthesized data through qualitative descriptions and quantitative random effects meta-analysis due to extensive heterogeneity.
    Results: A total of 36 studies conducted in the last 20 years were included for the qualitative analysis and four out of these studies were used to perform the meta-analysis. A significant decrease in naïve T cell subset was observed in older adults compared to young adults. Primary markers used to identify senescent cells were loss of CD28 and increased expression of CD57 and KLRG1 in terminally-differentiated memory T cell subset in older adults. Moreover, we observed an increase in proinflammatory cytokines and decrease in telomere length in old adult T cells. It was not possible to perform quantitative synthesis on cell markers, cytokines, and telomere length because of the significant variations between the groups, which is attributed to differences in protocols and unreported measurements, thus generating a high risk of bias.
    Conclusions: Heterogeneity among studies in terms of data report, measurement techniques and high risk of bias were major impediments for performing a robust statistical analysis that could aid the identification of eligible flow cytometry markers of immunosenescence phenotype in T cells.
    Keywords:  T cells; cytokines; flow cytometry; immunosenescence; immunosenescence markers
    DOI:  https://doi.org/10.3389/fimmu.2020.604591
  9. Nat Commun. 2021 02 03. 12(1): 769
    Tallón de Lara P, Castañón H, Vermeer M, Núñez N, Silina K, Sobottka B, Urdinez J, Cecconi V, Yagita H, Movahedian Attar F, Hiltbrunner S, Glarner I, Moch H, Tugues S, Becher B, van den Broek M.
      Some breast tumors metastasize aggressively whereas others remain dormant for years. The mechanism governing metastatic dormancy remains largely unknown. Through high-parametric single-cell mapping in mice, we identify a discrete population of CD39+PD-1+CD8+ T cells in primary tumors and in dormant metastasis, which is hardly found in aggressively metastasizing tumors. Using blocking antibodies, we find that dormancy depends on TNFα and IFNγ. Immunotherapy reduces the number of dormant cancer cells in the lungs. Adoptive transfer of purified CD39+PD-1+CD8+ T cells prevents metastatic outgrowth. In human breast cancer, the frequency of CD39+PD-1+CD8+ but not total CD8+ T cells correlates with delayed metastatic relapse after resection (disease-free survival), thus underlining the biological relevance of CD39+PD-1+CD8+ T cells for controlling experimental and human breast cancer. Thus, we suggest that a primary breast tumor could prime a systemic, CD39+PD-1+CD8+ T cell response that favors metastatic dormancy in the lungs.
    DOI:  https://doi.org/10.1038/s41467-021-21045-2
  10. Front Immunol. 2020 ;11 594620
    Watkinson F, Nayar SK, Rani A, Sakellariou CA, Elhage O, Papaevangelou E, Dasgupta P, Galustian C.
      Interleukin-15 (IL-15) is a cytokine that has been shown to expand CD8 T cell and natural killer (NK) cell populations, and therefore has potential for potentiating adoptive immune cell therapy for cancer. Previously, IL-15 has been shown to induce proliferation of CD8 memory T cells through activation of telomerase. Here, we investigated whether telomerase is also activated during the IL-15 mediated proliferation of NK and NKT-like (CD56+CD3+) cells. We also examined the extent that each of the three signaling pathways known to be stimulated by IL-2/IL-15 (JAK-STAT, PI3K-AKT Ras-RAF/MAPK) were activated and involved in the telomerase expression in the three cell types NK, NKT, or CD8 T cells. To assess cell proliferation and doubling, peripheral blood mononuclear cells (PBMCs) or isolated NK, NKT-like or CD8 T cells were incubated with varying concentrations of IL-15 or IL-2 for 7 days. CD8 T, NK, and NKT cell expansion was determined by fluorophore-conjugated antibody staining and flow cytometry. Cell doubling was investigated using carboxyfluorescein-succinimidyl-ester (CFSE). Telomerase expression was investigated by staining cells with anti-telomerase reverse transcriptase (anti-TERT). Telomerase activity in CD56+ and CD8 T cells was also measured via Telomerase Repeat Amplification Protocol (TRAP). Analysis of cellular expansion, proliferation and TERT expression concluded that IL-15 increased cellular growth of NK, NKT, and CD8 T cells more effectively than IL-2 using low or high doses. IL-15, increased TERT expression in NK and NKT cells by up to 2.5 fold, the same increase seen in CD8 T cells. IL-2 had effects on TERT expression only at high doses (100-1000 ng/ml). Proteome profiling identified that IL-15 activated selected signaling proteins in the three pathways (JAK-STAT, PI3K-AKT, Ras-MAPK) known to mediate IL-2/IL-15 signaling, more strongly than IL-2. Evaluation by signaling pathway inhibitors revealed that JAK/STAT and PI3K/AKT pathways are important in IL-15's ability to upregulate TERT expression in NK and NKT cells, whereas all three pathways were involved in CD8 T cell TERT expression. In conclusion, this study shows that IL-15 potently stimulates TERT upregulation in NK and NKT cells in addition to CD8 T cells and is therefore a valuable tool for adoptive cell therapies.
    Keywords:  adoptive cell therapy; cell-signaling; interleukin-15; interleukin-2; telomerase
    DOI:  https://doi.org/10.3389/fimmu.2020.594620
  11. Sci Adv. 2021 Jan;pii: eabe1174. [Epub ahead of print]7(4):
    Kilgour MK, MacPherson S, Zacharias LG, Ellis AE, Sheldon RD, Liu EY, Keyes S, Pauly B, Carleton G, Allard B, Smazynski J, Williams KS, Watson PH, Stagg J, Nelson BH, DeBerardinis RJ, Jones RG, Hamilton PT, Lum JJ.
      Immune regulatory metabolites are key features of the tumor microenvironment (TME), yet with a few exceptions, their identities remain largely unknown. Here, we profiled tumor and T cells from tumor and ascites of patients with high-grade serous carcinoma (HGSC) to uncover the metabolomes of these distinct TME compartments. Cells within the ascites and tumor had pervasive metabolite differences, with a notable enrichment in 1-methylnicotinamide (MNA) in T cells infiltrating the tumor compared with ascites. Despite the elevated levels of MNA in T cells, the expression of nicotinamide N-methyltransferase, the enzyme that catalyzes the transfer of a methyl group from S-adenosylmethionine to nicotinamide, was restricted to fibroblasts and tumor cells. Functionally, MNA induces T cells to secrete the tumor-promoting cytokine tumor necrosis factor alpha. Thus, TME-derived MNA contributes to the immune modulation of T cells and represents a potential immunotherapy target to treat human cancer.
    DOI:  https://doi.org/10.1126/sciadv.abe1174
  12. J Biol Chem. 2020 May 22. pii: S0021-9258(17)50269-0. [Epub ahead of print]295(21): 7362-7375
    Croft T, Venkatakrishnan P, James Theoga Raj C, Groth B, Cater T, Salemi MR, Phinney B, Lin SJ.
      NAD+ is an essential metabolite participating in cellular biochemical processes and signaling. The regulation and interconnection among multiple NAD+ biosynthesis pathways are incompletely understood. Yeast (Saccharomyces cerevisiae) cells lacking the N-terminal (Nt) protein acetyltransferase complex NatB exhibit an approximate 50% reduction in NAD+ levels and aberrant metabolism of NAD+ precursors, changes that are associated with a decrease in nicotinamide mononucleotide adenylyltransferase (Nmnat) protein levels. Here, we show that this decrease in NAD+ and Nmnat protein levels is specifically due to the absence of Nt-acetylation of Nmnat (Nma1 and Nma2) proteins and not of other NatB substrates. Nt-acetylation critically regulates protein degradation by the N-end rule pathways, suggesting that the absence of Nt-acetylation may alter Nmnat protein stability. Interestingly, the rate of protein turnover (t½) of non-Nt-acetylated Nmnats did not significantly differ from those of Nt-acetylated Nmnats. Accordingly, deletion or depletion of the N-end rule pathway ubiquitin E3 ligases in NatB mutants did not restore NAD+ levels. Next, we examined whether the status of Nt-acetylation would affect the translation of Nmnats, finding that the absence of Nt-acetylation does not significantly alter the polysome formation rate on Nmnat mRNAs. However, we observed that NatB mutants have significantly reduced Nmnat protein maturation. Our findings indicate that the reduced Nmnat levels in NatB mutants are mainly due to inefficient protein maturation. Nmnat activities are essential for all NAD+ biosynthesis routes, and understanding the regulation of Nmnat protein homeostasis may improve our understanding of the molecular basis and regulation of NAD+ metabolism.
    Keywords:  NAD biosynthesis; NAD homeostasis; NatB; cell metabolism; cell signaling; metabolic regulation; nicotinamide mononucleotide adenylyltransferase (Nmnat); protein acetylation; yeast genetics; yeast metabolism
    DOI:  https://doi.org/10.1074/jbc.RA119.011667
  13. Nat Genet. 2021 Feb;53(2): 215-229
    Betto RM, Diamante L, Perrera V, Audano M, Rapelli S, Lauria A, Incarnato D, Arboit M, Pedretti S, Rigoni G, Guerineau V, Touboul D, Stirparo GG, Lohoff T, Boroviak T, Grumati P, Soriano ME, Nichols J, Mitro N, Oliviero S, Martello G.
      Naive epiblast and embryonic stem cells (ESCs) give rise to all cells of adults. Such developmental plasticity is associated with genome hypomethylation. Here, we show that LIF-Stat3 signaling induces genomic hypomethylation via metabolic reconfiguration. Stat3-/- ESCs show decreased α-ketoglutarate production from glutamine, leading to increased Dnmt3a and Dnmt3b expression and DNA methylation. Notably, genome methylation is dynamically controlled through modulation of α-ketoglutarate availability or Stat3 activation in mitochondria. Alpha-ketoglutarate links metabolism to the epigenome by reducing the expression of Otx2 and its targets Dnmt3a and Dnmt3b. Genetic inactivation of Otx2 or Dnmt3a and Dnmt3b results in genomic hypomethylation even in the absence of active LIF-Stat3. Stat3-/- ESCs show increased methylation at imprinting control regions and altered expression of cognate transcripts. Single-cell analyses of Stat3-/- embryos confirmed the dysregulated expression of Otx2, Dnmt3a and Dnmt3b as well as imprinted genes. Several cancers display Stat3 overactivation and abnormal DNA methylation; therefore, the molecular module that we describe might be exploited under pathological conditions.
    DOI:  https://doi.org/10.1038/s41588-020-00770-2
  14. Nature. 2021 Feb;590(7844): 57-66
    Kraus F, Roy K, Pucadyil TJ, Ryan MT.
      Mitochondria form dynamic networks in the cell that are balanced by the flux of iterative fusion and fission events of the organelles. It is now appreciated that mitochondrial fission also represents an end-point event in a signalling axis that allows cells to sense and respond to external cues. The fission process is orchestrated by membrane-associated adaptors, influenced by organellar and cytoskeletal interactions and ultimately executed by the dynamin-like GTPase DRP1. Here we invoke the framework of the 'mitochondrial divisome', which is conceptually and operationally similar to the bacterial cell-division machinery. We review the functional and regulatory aspects of the mitochondrial divisome and, within this framework, parse the core from the accessory machinery. In so doing, we transition from a phenomenological to a mechanistic understanding of the fission process.
    DOI:  https://doi.org/10.1038/s41586-021-03214-x