bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021‒01‒24
twenty papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research
  1. Distinct metabolic programs established in the thymus control effector functions of γδ T cell subsets in tumor microenvironments.
  2. Low-dose decitabine priming endows CAR T cells with enhanced and persistent antitumour potential via epigenetic reprogramming.
  3. T cell receptor-dependent S-acylation of ZAP-70 controls activation of T cells.
  4. CMV-independent increase in CD27-CD28+ CD8+ EMRA T cells is inversely related to mortality in octogenarians.
  5. Functional Heterogeneity and Therapeutic Targeting of Tissue-Resident Memory T Cells.
  6. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis.
  7. Recent advances and discoveries in the mechanisms and functions of CAR T cells.
  8. The immune response of T cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke.
  9. Emr1 regulates the number of foci of the endoplasmic reticulum-mitochondria encounter structure complex.
  10. Exhausted T cells in systemic lupus erythematosus patients in long-standing remission.
  11. Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration.
  12. Aging and CMV discordance are associated with increased immune diversity between monozygotic twins.
  13. Normal aging induces PD-1-enriched exhausted microglia and A1-like reactive astrocytes in the hypothalamus.
  14. Human intestinal tissue-resident memory T cells comprise transcriptionally and functionally distinct subsets.
  15. Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity.
  16. NAD precursors, mitochondria targeting compounds and ADPribosylation inhibitors in treatment of inflammatory diseases and cancer.
  17. Poly(ADP-Ribose) polymerase 1 regulates mitochondrial DNA repair in a metabolism-dependent manner.
  18. Rethinking immune checkpoint blockade: 'Beyond the T cell'.
  19. Reversal of immune-cell shutdown protects the ageing brain.
  20. Hematopoietic versus Solid Cancers and T Cell Dysfunction: Looking for Similarities and Distinctions.
  1. Nat Immunol. 2021 Jan 18.
    Distinct metabolic programs established in the thymus control effector functions of γδ T cell subsets in tumor microenvironments.
    Noella Lopes, Claire McIntyre, Stefania Martin, Mathilde Raverdeau, Nital Sumaria, Ayano C Kohlgruber, Gina J Fiala, Leandro Z Agudelo, Lydia Dyck, Harry Kane, Aaron Douglas, Stephen Cunningham, Hannah Prendeville, Roisin Loftus, Colleen Carmody, Philippe Pierre, Manolis Kellis, Michael Brenner, Rafael J Argüello, Bruno Silva-Santos, Daniel J Pennington, Lydia Lynch.
      Metabolic programming controls immune cell lineages and functions, but little is known about γδ T cell metabolism. Here, we found that γδ T cell subsets making either interferon-γ (IFN-γ) or interleukin (IL)-17 have intrinsically distinct metabolic requirements. Whereas IFN-γ+ γδ T cells were almost exclusively dependent on glycolysis, IL-17+ γδ T cells strongly engaged oxidative metabolism, with increased mitochondrial mass and activity. These distinct metabolic signatures were surprisingly imprinted early during thymic development and were stably maintained in the periphery and within tumors. Moreover, pro-tumoral IL-17+ γδ T cells selectively showed high lipid uptake and intracellular lipid storage and were expanded in obesity and in tumors of obese mice. Conversely, glucose supplementation enhanced the antitumor functions of IFN-γ+ γδ T cells and reduced tumor growth upon adoptive transfer. These findings have important implications for the differentiation of effector γδ T cells and their manipulation in cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-020-00848-3
  2. Nat Commun. 2021 01 18. 12(1): 409
    Low-dose decitabine priming endows CAR T cells with enhanced and persistent antitumour potential via epigenetic reprogramming.
    Yao Wang, Chuan Tong, Hanren Dai, Zhiqiang Wu, Xiao Han, Yelei Guo, Deyun Chen, Jianshu Wei, Dongdong Ti, Zongzhi Liu, Qian Mei, Xiang Li, Liang Dong, Jing Nie, Yajing Zhang, Weidong Han.
      Insufficient eradication capacity and dysfunction are common occurrences in T cells that characterize cancer immunotherapy failure. De novo DNA methylation promotes T cell exhaustion, whereas methylation inhibition enhances T cell rejuvenation in vivo. Decitabine, a DNA methyltransferase inhibitor approved for clinical use, may provide a means of modifying exhaustion-associated DNA methylation programmes. Herein, anti-tumour activities, cytokine production, and proliferation are enhanced in decitabine-treated chimeric antigen receptor T (dCAR T) cells both in vitro and in vivo. Additionally, dCAR T cells can eradicate bulky tumours at a low-dose and establish effective recall responses upon tumour rechallenge. Antigen-expressing tumour cells trigger higher expression levels of memory-, proliferation- and cytokine production-associated genes in dCAR T cells. Tumour-infiltrating dCAR T cells retain a relatively high expression of memory-related genes and low expression of exhaustion-related genes in vivo. In vitro administration of decitabine may represent an option for the generation of CAR T cells with improved anti-tumour properties.
    DOI:  https://doi.org/10.1038/s41467-020-20696-x
  3. J Biol Chem. 2021 Jan 19. pii: S0021-9258(21)00080-6. [Epub ahead of print] 100311
    T cell receptor-dependent S-acylation of ZAP-70 controls activation of T cells.
    Ritika Tewari, Bieerkehazhi Shayahati, Ying Fan, Askar M Akimzhanov.
      ZAP-70 is a tyrosine kinase essential for T cell immune responses. Upon engagement of the T cell receptor (TCR), ZAP-70 is recruited to the specialized plasma membrane domains, becomes activated and is released to phosphorylate its laterally segregated targets. A shift in ZAP-70 distribution at the plasma membrane is recognized as a critical step in TCR signal transduction and amplification. However, the molecular mechanism supporting stimulation-dependent plasma membrane compartmentalization of ZAP-70 remains poorly understood. In this study, we identified previously uncharacterized lipidation (S-acylation) of ZAP-70 using Acyl-Biotin Exchange (ABE) assay, a technique that selectively captures S-acylated proteins. We found that this post-translational modification of ZAP-70 is dispensable for its enzymatic activity. However, the lipidation-deficient mutant of ZAP-70 failed to propagate the TCR pathway suggesting that S-acylation is essential for ZAP-70 interaction with its protein substrates. The kinetics of ZAP-70 S-acylation were consistent with TCR signaling events indicating that agonist-induced S-acylation is a part of the signaling mechanism controlling T cell activation and function. Taken together, our results suggest that TCR-induced S-acylation of ZAP-70 can serve as a critical regulator of T cell-mediated immunity.
    Keywords:  S-acylation; T cell; acyltransferase; palmitoylation; signal transduction
    DOI:  https://doi.org/10.1016/j.jbc.2021.100311
  4. NPJ Aging Mech Dis. 2020 Jan 21. 6(1): 3
    CMV-independent increase in CD27-CD28+ CD8+ EMRA T cells is inversely related to mortality in octogenarians.
    Carmen Martin-Ruiz, Jedrzej Hoffmann, Evgeniya Shmeleva, Thomas von Zglinicki, Gavin Richardson, Lilia Draganova, Rachael Redgrave, Joanna Collerton, Helen Arthur, Bernard Keavney, Ioakim Spyridopoulos.
      Cytomegalovirus (CMV) seropositivity in adults has been linked to increased cardiovascular disease burden. Phenotypically, CMV infection leads to an inflated CD8 T-lymphocyte compartment. We employed a 8-colour flow cytometric protocol to analyse circulating T cells in 597 octogenarians from the same birth cohort together with NT-proBNP measurements and followed all participants over 7 years. We found that, independent of CMV serostatus, a high number of CD27-CD28+ CD8 EMRA T-lymphocytes (TEMRA) protected from all-cause death after adjusting for known risk factors, such as heart failure, frailty or cancer (Hazard ratio 0.66 for highest vs lowest tertile; confidence interval 0.51-0.86). In addition, CD27-CD28+ CD8 EMRA T-lymphocytes protected from both, non-cardiovascular (hazard ratio 0.59) and cardiovascular death (hazard ratio 0.65). In aged mice treated with the senolytic navitoclax, in which we have previously shown a rejuvenated cardiac phenotype, CD8 effector memory cells are decreased, further indicating that alterations in T cell subpopulations are associated with cardiovascular ageing. Future studies are required to show whether targeting immunosenescence will lead to enhanced life- or healthspan.
    DOI:  https://doi.org/10.1038/s41514-019-0041-y
  5. Cells. 2021 Jan 15. pii: E164. [Epub ahead of print]10(1):
    Functional Heterogeneity and Therapeutic Targeting of Tissue-Resident Memory T Cells.
    Esmé T I van der Gracht, Felix M Behr, Ramon Arens.
      Tissue-resident memory T (TRM) cells mediate potent local innate and adaptive immune responses and provide long-lasting protective immunity. TRM cells localize to many different tissues, including barrier tissues, and play a crucial role in protection against infectious and malignant disease. The formation and maintenance of TRM cells are influenced by numerous factors, including inflammation, antigen triggering, and tissue-specific cues. Emerging evidence suggests that these signals also contribute to heterogeneity within the TRM cell compartment. Here, we review the phenotypic and functional heterogeneity of CD8+ TRM cells at different tissue sites and the molecular determinants defining CD8+ TRM cell subsets. We further discuss the possibilities of targeting the unique cell surface molecules, cytokine and chemokine receptors, transcription factors, and metabolic features of TRM cells for therapeutic purposes. Their crucial role in immune protection and their location at the frontlines of the immune defense make TRM cells attractive therapeutic targets. A better understanding of the possibilities to selectively modulate TRM cell populations may thus improve vaccination and immunotherapeutic strategies employing these potent immune cells.
    Keywords:  T cells; heterogeneity; immunotherapy; therapeutic targeting; tissue residency
    DOI:  https://doi.org/10.3390/cells10010164
  6. Nat Commun. 2021 01 20. 12(1): 470
    MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis.
    Joseph C Reynolds, Rochelle W Lai, Jonathan S T Woodhead, James H Joly, Cameron J Mitchell, David Cameron-Smith, Ryan Lu, Pinchas Cohen, Nicholas A Graham, Bérénice A Benayoun, Troy L Merry, Changhan Lee.
      Healthy aging can be promoted by enhanced metabolic fitness and physical capacity. Mitochondria are chief metabolic organelles with strong implications in aging that also coordinate broad physiological functions, in part, using peptides that are encoded within their independent genome. However, mitochondrial-encoded factors that actively regulate aging are unknown. Here, we report that mitochondrial-encoded MOTS-c can significantly enhance physical performance in young (2 mo.), middle-age (12 mo.), and old (22 mo.) mice. MOTS-c can regulate (i) nuclear genes, including those related to metabolism and proteostasis, (ii) skeletal muscle metabolism, and (iii) myoblast adaptation to metabolic stress. We provide evidence that late-life (23.5 mo.) initiated intermittent MOTS-c treatment (3x/week) can increase physical capacity and healthspan in mice. In humans, exercise induces endogenous MOTS-c expression in skeletal muscle and in circulation. Our data indicate that aging is regulated by genes encoded in both of our co-evolved mitochondrial and nuclear genomes.
    DOI:  https://doi.org/10.1038/s41467-020-20790-0
  7. Nat Rev Cancer. 2021 Jan 22.
    Recent advances and discoveries in the mechanisms and functions of CAR T cells.
    Rebecca C Larson, Marcela V Maus.
      This Review discusses the major advances and changes made over the past 3 years to our understanding of chimeric antigen receptor (CAR) T cell efficacy and safety. Recently, the field has gained insight into how various molecular modules of the CAR influence signalling and function. We report on mechanisms of toxicity and resistance as well as novel engineering and pharmaceutical interventions to overcome these challenges. Looking forward, we discuss new targets and indications for CAR T cell therapy expected to reach the clinic in the next 1-2 years. We also consider some new studies that have implications for the future of CAR T cell therapies, including changes to manufacturing, allogeneic products and drug-regulatable CAR T cells.
    DOI:  https://doi.org/10.1038/s41568-020-00323-z
  8. J Neuroinflammation. 2021 Jan 18. 18(1): 25
    The immune response of T cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke.
    Tian-Yu Lei, Ying-Ze Ye, Xi-Qun Zhu, Daniel Smerin, Li-Juan Gu, Xiao-Xing Xiong, Hong-Fei Zhang, Zhi-Hong Jian.
      Through considerable effort in research and clinical studies, the immune system has been identified as a participant in the onset and progression of brain injury after ischaemic stroke. Due to the involvement of all types of immune cells, the roles of the immune system in stroke pathology and associated effects are complicated. Past research concentrated on the functions of monocytes and neutrophils in the pathogenesis of ischaemic stroke and tried to demonstrate the mechanisms of tissue injury and protection involving these immune cells. Within the past several years, an increasing number of studies have elucidated the vital functions of T cells in the innate and adaptive immune responses in both the acute and chronic phases of ischaemic stroke. Recently, the phenotypes of T cells with proinflammatory or anti-inflammatory function have been demonstrated in detail. T cells with distinctive phenotypes can also influence cerebral inflammation through various pathways, such as regulating the immune response, interacting with brain-resident immune cells and modulating neurogenesis and angiogenesis during different phases following stroke. In view of the limited treatment options available following stroke other than tissue plasminogen activator therapy, understanding the function of immune responses, especially T cell responses, in the post-stroke recovery period can provide a new therapeutic direction. Here, we discuss the different functions and temporal evolution of T cells with different phenotypes during the acute and chronic phases of ischaemic stroke. We suggest that modulating the balance between the proinflammatory and anti-inflammatory functions of T cells with distinct phenotypes may become a potential therapeutic approach that reduces the mortality and improves the functional outcomes and prognosis of patients suffering from ischaemic stroke.
    Keywords:  Immune responses; Ischaemic stroke; T cell subsets
    DOI:  https://doi.org/10.1186/s12974-020-02057-z
  9. Nat Commun. 2021 Jan 22. 12(1): 521
    Emr1 regulates the number of foci of the endoplasmic reticulum-mitochondria encounter structure complex.
    Faiz Rasul, Fan Zheng, Fenfen Dong, Jiajia He, Ling Liu, Wenyue Liu, Javairia Yousuf Cheema, Wenfan Wei, Chuanhai Fu.
      The endoplasmic reticulum-mitochondria encounter structure (ERMES) complex creates contact sites between the endoplasmic reticulum and mitochondria, playing crucial roles in interorganelle communication, mitochondrial fission, mtDNA inheritance, lipid transfer, and autophagy. The mechanism regulating the number of ERMES foci within the cell remains unclear. Here, we demonstrate that the mitochondrial membrane protein Emr1 contributes to regulating the number of ERMES foci. We show that the absence of Emr1 significantly decreases the number of ERMES foci. Moreover, we find that Emr1 interacts with the ERMES core component Mdm12 and colocalizes with Mdm12 on mitochondria. Similar to ERMES mutant cells, cells lacking Emr1 display defective mitochondrial morphology and impaired mitochondrial segregation, which can be rescued by an artificial tether capable of linking the endoplasmic reticulum and mitochondria. We further demonstrate that the cytoplasmic region of Emr1 is required for regulating the number of ERMES foci. This work thus reveals a crucial regulatory protein necessary for ERMES functions and provides mechanistic insights into understanding the dynamic regulation of endoplasmic reticulum-mitochondria communication.
    DOI:  https://doi.org/10.1038/s41467-020-20866-x
  10. Clin Exp Immunol. 2021 Jan 21.
    Exhausted T cells in systemic lupus erythematosus patients in long-standing remission.
    Guadalupe Lima, Francisco Treviño-Tello, Yemil Atisha-Fregoso, Luis Llorente, Hilda Fragoso-Loyo, Juan Jakez-Ocampo.
      The mechanisms that drives SLE patients to achieve remission are unknown, one possible explanation might be T cell exhaustion. The aim of the present study was to measure CD4+ and CD8+ T cell exhaustion in SLE patients in prolonged remission (PR-SLE) and compared them with patients with active SLE (Act-SLE) and healthy subjects. We included 15 PR-SLE patients, 15 Act-SLE and 29 healthy subjects. T-cell exhaustion was determined by flow cytometry according to the expression of PD-1, Tim-3, 2B4, EOMES and T-bet in CD4+ and CD8+ T cells. Dimensionality reduction using the t-Distributed Stochastic Neighbor Embedding algorithm and Clustering Analysis was used for the identification of relevant populations. Percentages of CD3+, CD4+ and CD8+ T cells were similar among groups. We identified five subpopulations of CD8+ and seven of CD4+ cells. The CD4+Tbet+CD45RO+ cells identified in the unsupervised analysis were significantly increased in PR-SLE vs Act-SLE (median: 10.20, IQR: 1.74-30.50 vs. 1.68, IQR: 0.4-2.83; p<0.01). CD4+EOMES+ cells were also increased in PR-SLE vs Act-SLE (5.24, IQR: 3.38-14.70 vs. 1.39, IQR: 0.48-2.87; p<0.001). CD8+ EOMES+ cells were increased in PR-SLE vs Act-SLE (37.6, IQR: 24.9-53.2 vs 8.13, IQR: 2.33-20.5; p<0.001). Exhausted and activated T cells presented an increased frequency of PD-1, CD57 and EOMES in SLE patient's vs healthy subjects. Some subpopulations of T cells expressing markers associated with exhaustion are increased in patients in remission, supporting T-cell exhaustion as a tolerance mechanism in SLE. Exhaustion of specific populations of T cells might represent a potential therapeutic tool that will contribute to the goal of achieving sustained remission in these patients.
    Keywords:  Clinical remission in SLE; Clustering analysis; T cell exhaustion
    DOI:  https://doi.org/10.1111/cei.13577
  11. J Neuroinflammation. 2021 Jan 22. 18(1): 32
    Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration.
    Keng Siang Lee, Shuxiao Lin, David A Copland, Andrew D Dick, Jian Liu.
      Age-related macular degeneration (AMD), a degenerative disease in the central macula area of the neuroretina and the supporting retinal pigment epithelium, is the most common cause of vision loss in the elderly. Although advances have been made, treatment to prevent the progressive degeneration is lacking. Besides the association of innate immune pathway genes with AMD susceptibility, environmental stress- and cellular senescence-induced alterations in pathways such as metabolic functions and inflammatory responses are also implicated in the pathophysiology of AMD. Cellular senescence is an adaptive cell process in response to noxious stimuli in both mitotic and postmitotic cells, activated by tumor suppressor proteins and prosecuted via an inflammatory secretome. In addition to physiological roles in embryogenesis and tissue regeneration, cellular senescence is augmented with age and contributes to a variety of age-related chronic conditions. Accumulation of senescent cells accompanied by an impairment in the immune-mediated elimination mechanisms results in increased frequency of senescent cells, termed "chronic" senescence. Age-associated senescent cells exhibit abnormal metabolism, increased generation of reactive oxygen species, and a heightened senescence-associated secretory phenotype that nurture a proinflammatory milieu detrimental to neighboring cells. Senescent changes in various retinal and choroidal tissue cells including the retinal pigment epithelium, microglia, neurons, and endothelial cells, contemporaneous with systemic immune aging in both innate and adaptive cells, have emerged as important contributors to the onset and development of AMD. The repertoire of senotherapeutic strategies such as senolytics, senomorphics, cell cycle regulation, and restoring cell homeostasis targeted both at tissue and systemic levels is expanding with the potential to treat a spectrum of age-related diseases, including AMD.
    Keywords:  Cellular senescence; Immune aging; Macular degeneration; Microglia; Neuron; Retinal pigment epithelium; SASP
    DOI:  https://doi.org/10.1186/s12974-021-02088-0
  12. Immun Ageing. 2021 Jan 18. 18(1): 5
    Aging and CMV discordance are associated with increased immune diversity between monozygotic twins.
    Zheng Yan, Holden T Maecker, Petter Brodin, Unni C Nygaard, Shu Chen Lyu, Mark M Davis, Kari C Nadeau, Sandra Andorf.
      BACKGROUND: Broadly, much of variance in immune system phenotype has been linked to the influence of non-heritable factors rather than genetics. In particular, two non-heritable factors: aging and human cytolomegavirus (CMV) infection, have been known to account for significant inter-individual immune variance. However, many specific relationships between them and immune composition remain unclear, especially between individuals over narrower age ranges. Further exploration of these relationships may be useful for informing personalized intervention development.RESULTS: To address this need, we evaluated 41 different cell type frequencies by mass cytometry and identified their relationships with aging and CMV seropositivity. Analyses were done using 60 healthy individuals, including 23 monozygotic twin pairs, categorized into young (12-31 years) and middle-aged (42-59 years). Aging and CMV discordance were associated with increased immune diversity between monozygotic twins overall, and particularly strongly in various T cell populations. Notably, we identified 17 and 11 cell subset frequencies as relatively influenced and uninfluenced by non-heritable factors, respectively, with results that largely matched those from studies on older-aged cohorts. Next, CD4+ T cell frequency was shown to diverge with age in twins, but with lower slope than in demographically similar non-twins, suggesting that much inter-individual variance in this cell type can be attributed to interactions between genetic and environmental factors. Several cell frequencies previously associated with memory inflation, such as CD27- CD8+ T cells and CD161+ CD4+ T cells, were positively correlated with CMV seropositivity, supporting findings that CMV infection may incur rapid aging of the immune system.
    CONCLUSIONS: Our study confirms previous findings that aging, even within a relatively small age range and by mid-adulthood, and CMV seropositivity, both contribute significantly to inter-individual immune diversity. Notably, we identify several key immune cell subsets that vary considerably with aging, as well as others associated with memory inflation which correlate with CMV seropositivity.
    Keywords:  Aging; Cytomegalovirus; Human immunology; Mass cytometry (CyTOF); Monozygotic twins
    DOI:  https://doi.org/10.1186/s12979-021-00216-1
  13. Biochem Biophys Res Commun. 2021 Jan 15. pii: S0006-291X(20)32273-7. [Epub ahead of print]541 22-29
    Normal aging induces PD-1-enriched exhausted microglia and A1-like reactive astrocytes in the hypothalamus.
    Yukari Suda, Toshihisa Nakashima, Hiroaki Matsumoto, Daisuke Sato, Satoshi Nagano, Haruka Mikata, Sara Yoshida, Kenichi Tanaka, Yusuke Hamada, Naoko Kuzumaki, Minoru Narita.
      Hypothalamic aging is considered to be critical for systemic aging, and the accumulation of "exhausted glial cells" in the hypothalamus may contribute to brain dysfunction. In this study, we used normal aging mice and investigated aging-specific transcriptional identities of microglia and astrocytes in the hypothalamus. We confirmed that normal aging promoted anxiety, induced impairment of motor coordination and reduced physical strength of muscle in mice. To investigate the senescence of hypothalamic glial cells, we isolated CD11b-positive microglia and ACSA-2-positive astrocytes from the hypothalamus of aged mice using magnetic-activated cell sorting (MACS). The mRNA level of p16INK4A was dramatically increased in the hypothalamic microglia of aged mice compared to young mice. Furthermore, the expression of programmed cell death 1 (PD-1) as well as A1-like astrocyte mediators in the hypothalamic microglia was dramatically induced by aging, indicating that normal aging may produce PD-1-enriched "exhausted microglia" in the hypothalamus. Furthermore, neuroinflammatory A1-like reactive astrocytes with a p16INK4A-positive senescent state were predominantly detected in the hypothalamus of aged mice. Exhausted microglia were also detected in the prefrontal cortex of aged mice, whereas astrocytic neuroinflammation was milder than that observed in the hypothalamus, even with p16INK4A-positive senescence. These results suggest that the production of PD-1-enriched exhausted and senescent microglia and neuroinflammatory A1-like reactive astrocytes in the hypothalamus may partly contribute to aging-related emotional and physical dyscoordination.
    DOI:  https://doi.org/10.1016/j.bbrc.2020.12.086
  14. Cell Rep. 2021 Jan 19. pii: S2211-1247(20)31650-8. [Epub ahead of print]34(3): 108661
    Human intestinal tissue-resident memory T cells comprise transcriptionally and functionally distinct subsets.
    Michael E B FitzPatrick, Nicholas M Provine, Lucy C Garner, Kate Powell, Ali Amini, Sophie L Irwin, Helen Ferry, Tim Ambrose, Peter Friend, Georgios Vrakas, Srikanth Reddy, Elizabeth Soilleux, Paul Klenerman, Philip J Allan.
      Tissue-resident memory T (TRM) cells provide key adaptive immune responses in infection, cancer, and autoimmunity. However, transcriptional heterogeneity of human intestinal TRM cells remains undefined. Here, we investigate transcriptional and functional heterogeneity of human TRM cells through study of donor-derived TRM cells from intestinal transplant recipients. Single-cell transcriptional profiling identifies two transcriptional states of CD8+ TRM cells, delineated by ITGAE and ITGB2 expression. We define a transcriptional signature discriminating these populations, including differential expression of cytotoxicity- and residency-associated genes. Flow cytometry of recipient-derived cells infiltrating the graft, and lymphocytes from healthy gut, confirm these CD8+ TRM phenotypes. CD8+ CD69+CD103+ TRM cells produce interleukin-2 (IL-2) and demonstrate greater polyfunctional cytokine production, whereas β2-integrin+CD69+CD103- TRM cells have higher granzyme expression. Analysis of intestinal CD4+ T cells identifies several parallels, including a β2-integrin+ population. Together, these results describe the transcriptional, phenotypic, and functional heterogeneity of human intestinal CD4+ and CD8+ TRM cells.
    Keywords:  CD103; T cell; Tissue resident; human; intestinal transplantation; intestine; residency; transplant; β2-integrin
    DOI:  https://doi.org/10.1016/j.celrep.2020.108661
  15. Science. 2021 01 22. 371(6527): 405-410
    Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity.
    Ke Xu, Na Yin, Min Peng, Efstathios G Stamatiades, Amy Shyu, Peng Li, Xian Zhang, Mytrang H Do, Zhaoquan Wang, Kristelle J Capistrano, Chun Chou, Andrew G Levine, Alexander Y Rudensky, Ming O Li.
      Infection triggers expansion and effector differentiation of T cells specific for microbial antigens in association with metabolic reprograming. We found that the glycolytic enzyme lactate dehydrogenase A (LDHA) is induced in CD8+ T effector cells through phosphoinositide 3-kinase (PI3K) signaling. In turn, ablation of LDHA inhibits PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1, causing defective antimicrobial immunity. LDHA deficiency cripples cellular redox control and diminishes adenosine triphosphate (ATP) production in effector T cells, resulting in attenuated PI3K signaling. Thus, nutrient metabolism and growth factor signaling are highly integrated processes, with glycolytic ATP serving as a rheostat to gauge PI3K-Akt-Foxo1 signaling in the control of T cell immunity. Such a bioenergetic mechanism for the regulation of signaling may explain the Warburg effect.
    DOI:  https://doi.org/10.1126/science.abb2683
  16. Curr Med Chem. 2021 Jan 18.
    NAD precursors, mitochondria targeting compounds and ADPribosylation inhibitors in treatment of inflammatory diseases and cancer.
    Palmiro Poltronieri, Valeria Mezzolla, Ammad Ahmad Farooqi, Maria Di Girolamo.
      Mitochondrial dysfunction and oxidative stress are prominent features of a plethora of human disorders. Dysregulation of mitochondrial functions represents a common pathogenic mechanism of diseases such as neurodegenerative disorders and cancer. The maintenance of the Nicotinamide adenine dinucleotide (NAD+ ) pool, and a positive NAD+ /NADH ratio, are essential for mitochondrial and cell functions. The synthesis and degradation of NAD+ and transport of its key intermediates among cell compartments play an important role to maintain optimal NAD levels, for regulation of NAD+ -utilizing enzymes, such as sirtuins (Sirt), poly-ADP-ribose polymerases, and CD38/157 enzymes, either intracellularly as well as extracellularly. In this review, we present and discuss the links between NAD+ , NAD+ -consuming enzymes, mitochondria functions, and diseases. Attempts to treat various diseases with supplementation of NAD+ cycling intermediates and inhibitors of sirtuins and ADP-ribosyl transferases may highlight a possible therapeutic approach for therapy of cancer and neurodegenerative diseases.
    Keywords:  ADP-ribosyl transferases; NAD cycling; compartmentalization; nicotinamide; nicotinamide mononucleotide; nicotinamide riboside; sirtuins
    DOI:  https://doi.org/10.2174/0929867328666210118152653
  17. J Biol Chem. 2021 Jan 19. pii: S0021-9258(21)00078-8. [Epub ahead of print] 100309
    Poly(ADP-Ribose) polymerase 1 regulates mitochondrial DNA repair in a metabolism-dependent manner.
    Geoffrey K Herrmann, William K Russell, Nisha J Garg, Y Whitney Yin.
      Mitochondral DNA is located in organelle that house essential metablic reactions and contain high reactive oxygen species. Therefore, mitochondrial DNA suffers more oxidative damage than its nuclear counterpart. Formation of a repair enzyme complex is beneficial to DNA repair. Recent studies have shown that mitochondrial DNA polymerase (Pol γ) and poly(ADP-ribose) polymerase 1 (PARP1) were found in the same complex along with other mitochondrial DNA repair enzymes and mitochondrial PARP1 level is correlated with mtDNA integrity. However, the molecular basis for the functional connection between Pol γ and PARP1 has not yet been elucidated because cellular functions of PARP1 in DNA repair are intertwined with metabolism via NAD+ (nicotinamide adenosine dinucleotide), the substrate of PARP1 and a metabolic cofactor. To dissect the direct effect of PARP1 on mtDNA from the secondary perturbation of metabolism, we report here biochemical studies that recapitulated Pol γ PARylation observed in cells and showed that PARP1 regulates Pol γ activity during DNA repair in a metabolic cofactor NAD+ (nicotinamide adenosine dinucleotide)-dependent manner. In the absence of NAD+, PARP1 completely inhibits Pol γ, while increasing NAD+ levels to a physiological concentration that enables Pol γ to resume maximum repair activity. Because cellular NAD+ levels are linked to metabolism and to ATP production via oxidative phosphorylation, our results suggest that mtDNA damage repair is coupled to cellular metabolic state and the integrity of the respiratory chain.
    Keywords:  ADP-ribosylation; DNA polymerase; DNA repair; DNA synthesis; post-translational modification (PTM); protein-DNA interaction; protein-protein interaction; western blot
    DOI:  https://doi.org/10.1016/j.jbc.2021.100309
  18. J Immunother Cancer. 2021 Jan;pii: e001460. [Epub ahead of print]9(1):
    Rethinking immune checkpoint blockade: 'Beyond the T cell'.
    Xiuting Liu, Graham D Hogg, David G DeNardo.
      The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.
    Keywords:  CTLA-4 Antigen; immunity; immunotherapy; innate; programmed cell death 1 receptor; tumor microenvironment
    DOI:  https://doi.org/10.1136/jitc-2020-001460
  19. Nature. 2021 Jan 20.
    Reversal of immune-cell shutdown protects the ageing brain.
    Jonas J Neher.
      
    Keywords:  Ageing; Immunology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-021-00063-6
  20. Cancers (Basel). 2021 Jan 14. pii: E284. [Epub ahead of print]13(2):
    Hematopoietic versus Solid Cancers and T Cell Dysfunction: Looking for Similarities and Distinctions.
    Chiara Montironi, Cristina Muñoz-Pinedo, Eric Eldering.
      Cancer cells escape, suppress and exploit the host immune system to sustain themselves, and the tumor microenvironment (TME) actively dampens T cell function by various mechanisms. Over the last years, new immunotherapeutic approaches, such as adoptive chimeric antigen receptor (CAR) T cell therapy and immune checkpoint inhibitors, have been successfully applied for refractory malignancies that could only be treated in a palliative manner previously. Engaging the anti-tumor activity of the immune system, including CAR T cell therapy to target the CD19 B cell antigen, proved to be effective in acute lymphocytic leukemia. In low-grade hematopoietic B cell malignancies, such as chronic lymphocytic leukemia, clinical outcomes have been tempered by cancer-induced T cell dysfunction characterized in part by a state of metabolic lethargy. In multiple myeloma, novel antigens such as BCMA and CD38 are being explored for CAR T cells. In solid cancers, T cell-based immunotherapies have been applied successfully to melanoma and lung cancers, whereas application in e.g., breast cancer lags behind and is modestly effective as yet. The main hurdles for CAR T cell immunotherapy in solid tumors are the lack of suitable antigens, anatomical inaccessibility, and T cell anergy due to immunosuppressive TME. Given the wide range of success and failure of immunotherapies in various cancer types, it is crucial to comprehend the underlying similarities and distinctions in T cell dysfunction. Hence, this review aims at comparing selected, distinct B cell-derived versus solid cancer types and at describing means by which malignant cells and TME might dampen T cell anti-tumor activity, with special focus on immunometabolism. Drawing a meaningful parallel between the efficacy of immunotherapy and the extent of T cell dysfunction will shed light on areas where we can improve immune function to battle cancer.
    Keywords:  T cell dysfunction; TME; immunotherapy; metabolism; microenvironment
    DOI:  https://doi.org/10.3390/cancers13020284
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