bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021–10–24
eleven papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. The metabolic roots of senescence: mechanisms and opportunities for intervention.
  2. Mitochondrial Contributions to Hematopoietic Stem Cell Aging.
  3. Unraveling the Multifaceted Nature of CD8 T Cell Exhaustion Provides the Molecular Basis for Therapeutic T Cell Reconstitution in Chronic Hepatitis B and C.
  4. 'Off-the-Shelf' Immunotherapy: Manufacture of CD8+ T Cells Derived from Hematopoietic Stem Cells.
  5. Overcoming TGFβ-mediated immune evasion in cancer.
  6. TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism.
  7. Regulation of T Cells in Cancer by Nitric Oxide.
  8. Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice.
  9. Impact of Selenium on Biomarkers and Clinical Aspects Related to Ageing. A Review.
  10. Mitochondrial Phospholipid Homeostasis Is Regulated by the i-AAA Protease PaIAP and Affects Organismic Aging.
  11. Mitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology.
  1. Nat Metab. 2021 Oct;3(10): 1290-1301
    The metabolic roots of senescence: mechanisms and opportunities for intervention.
    Christopher D Wiley, Judith Campisi.
      Cellular senescence entails a permanent proliferative arrest, coupled to multiple phenotypic changes. Among these changes is the release of numerous biologically active molecules collectively known as the senescence-associated secretory phenotype, or SASP. A growing body of literature indicates that both senescence and the SASP are sensitive to cellular and organismal metabolic states, which in turn can drive phenotypes associated with metabolic dysfunction. Here, we review the current literature linking senescence and metabolism, with an eye toward findings at the cellular level, including both metabolic inducers of senescence and alterations in cellular metabolism associated with senescence. Additionally, we consider how interventions that target either metabolism or senescent cells might influence each other and mitigate some of the pro-aging effects of cellular senescence. We conclude that the most effective interventions will likely break a degenerative feedback cycle by which cellular senescence promotes metabolic diseases, which in turn promote senescence.
    DOI:  https://doi.org/10.1038/s42255-021-00483-8
  2. Int J Mol Sci. 2021 Oct 15. pii: 11117. [Epub ahead of print]22(20):
    Mitochondrial Contributions to Hematopoietic Stem Cell Aging.
    Claudia Morganti, Keisuke Ito.
      Mitochondrial dysfunction and stem cell exhaustion are two hallmarks of aging. In the hematopoietic system, aging is linked to imbalanced immune response and reduced regenerative capacity in hematopoietic stem cells (HSCs), as well as an increased predisposition to a spectrum of diseases, including myelodysplastic syndrome and acute myeloid leukemia. Myeloid-biased differentiation and loss of polarity are distinct features of aged HSCs, which generally exhibit enhanced mitochondrial oxidative phosphorylation and increased production of reactive oxygen species (ROS), suggesting a direct role for mitochondria in the degenerative process. Here, we provide an overview of current knowledge of the mitochondrial mechanisms that contribute to age-related phenotypes in HSCs. These include mitochondrial ROS production, alteration/activation of mitochondrial metabolism, the quality control pathway of mitochondria, and inflammation. Greater understanding of the key machineries of HSC aging will allow us to identify new therapeutic targets for preventing, delaying, or even reversing aspects of this process.
    Keywords:  ROS; aging; hematopoiesis; hematopoietic stem cell; inflammation; mitochondrial metabolism; stem cell exhaustion
    DOI:  https://doi.org/10.3390/ijms222011117
  3. Cells. 2021 Sep 28. pii: 2563. [Epub ahead of print]10(10):
    Unraveling the Multifaceted Nature of CD8 T Cell Exhaustion Provides the Molecular Basis for Therapeutic T Cell Reconstitution in Chronic Hepatitis B and C.
    Valeria Barili, Andrea Vecchi, Marzia Rossi, Ilaria Montali, Camilla Tiezzi, Amalia Penna, Diletta Laccabue, Gabriele Missale, Paola Fisicaro, Carolina Boni.
      In chronic hepatitis B and C virus infections persistently elevated antigen levels drive CD8+ T cells toward a peculiar differentiation state known as T cell exhaustion, which poses crucial constraints to antiviral immunity. Available evidence indicates that T cell exhaustion is associated with a series of metabolic and signaling deregulations and with a very peculiar epigenetic status which all together lead to reduced effector functions. A clear mechanistic network explaining how intracellular metabolic derangements, transcriptional and signaling alterations so far described are interconnected in a comprehensive and unified view of the T cell exhaustion differentiation profile is still lacking. Addressing this issue is of key importance for the development of innovative strategies to boost host immunity in order to achieve viral clearance. This review will discuss the current knowledge in HBV and HCV infections, addressing how innate immunity, metabolic derangements, extensive stress responses and altered epigenetic programs may be targeted to restore functionality and responsiveness of virus-specific CD8 T cells in the context of chronic virus infections.
    Keywords:  HBV; HCV; T cell exhaustion; chronic hepatitis; immune-modulation
    DOI:  https://doi.org/10.3390/cells10102563
  4. Cells. 2021 Oct 02. pii: 2631. [Epub ahead of print]10(10):
    'Off-the-Shelf' Immunotherapy: Manufacture of CD8+ T Cells Derived from Hematopoietic Stem Cells.
    Nicholas Boyd, Kellie Cartledge, Huimin Cao, Vera Evtimov, Aleta Pupovac, Alan Trounson, Richard Boyd.
      Cellular immunotherapy is revolutionizing cancer treatment. However, autologous transplants are complex, costly, and limited by the number and quality of T cells that can be isolated from and expanded for re-infusion into each patient. This paper demonstrates a stromal support cell-free in vitro method for the differentiation of T cells from umbilical cord blood hematopoietic stem cells (HSCs). For each single HSC cell input, approximately 5 × 104 T cells were created with an initial five days of HSC expansion and subsequent T cell differentiation over 49 days. When the induced in vitro differentiated T cells were activated by cytokines and anti-CD3/CD28 beads, CD8+ T cell receptor (TCR) γδ+ T cells were preferentially generated and elicited cytotoxic function against ovarian cancer cells in vitro. This process of inducing de novo functional T cells offers a possible strategy to increase T cell yields, simplify manufacturing, and reduce costs with application potential for conversion into chimeric antigen receptor (CAR)-T cells for cancer immunotherapy and for allogeneic transplantation to restore immune competence.
    Keywords:  CD8+ T cells; HSC; differentiation; off-the-shelf immunotherapy
    DOI:  https://doi.org/10.3390/cells10102631
  5. Nat Rev Cancer. 2021 Oct 20.
    Overcoming TGFβ-mediated immune evasion in cancer.
    Daniele V F Tauriello, Elena Sancho, Eduard Batlle.
      Transforming growth factor-β (TGFβ) signalling controls multiple cell fate decisions during development and tissue homeostasis; hence, dysregulation of this pathway can drive several diseases, including cancer. Here we discuss the influence that TGFβ exerts on the composition and behaviour of different cell populations present in the tumour immune microenvironment, and the context-dependent functions of this cytokine in suppressing or promoting cancer. During homeostasis, TGFβ controls inflammatory responses triggered by exposure to the outside milieu in barrier tissues. Lack of TGFβ exacerbates inflammation, leading to tissue damage and cellular transformation. In contrast, as tumours progress, they leverage TGFβ to drive an unrestrained wound-healing programme in cancer-associated fibroblasts, as well as to suppress the adaptive immune system and the innate immune system. In consonance with this key role in reprogramming the tumour microenvironment, emerging data demonstrate that TGFβ-inhibitory therapies can restore cancer immunity. Indeed, this approach can synergize with other immunotherapies - including immune checkpoint blockade - to unleash robust antitumour immune responses in preclinical cancer models. Despite initial challenges in clinical translation, these findings have sparked the development of multiple therapeutic strategies that inhibit the TGFβ pathway, many of which are currently in clinical evaluation.
    DOI:  https://doi.org/10.1038/s41568-021-00413-6
  6. Front Immunol. 2021 ;12 688961
    TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism.
    Qi Shao, Lei Wang, Maoling Yuan, Xiaohong Jin, Zhiming Chen, Changping Wu.
      T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immunosuppressive receptor expressed on the surface of immune cells, suppressing immune responses by activating the intracellular negative regulatory signals. TIGIT plays an important role in the pathogenesis of various tumors, but its immune escape in colorectal cancer remains unclear. We found that the proportion of CD3+TIGIT+ T cells was increased in peripheral blood and cancer tissue in colorectal cancer patients when compared with the healthy donors. These cells exhibited functional defects, low proliferative activity, impaired cytokine production and reduced glucose metabolism. A strong association was also observed between the elevated TIGIT expression and poor prognosis in this cohort. In the in vitro co-culture assays of T cells and tumor cells, the suppressed glucose metabolic activity of T cells was reversed by TIGIT blockade. In addition, this blockade induced the apoptosis and reduced G2/M transit in tumor cells. The antitumor efficacy of TIGIT Ab therapy was further demonstrated in a human colorectal xenograft mice model while co-blockers of TIGIT and PD-1 exhibited synergistic suppressing effects on tumor growth. These results suggest that while TIGIT induces CD3+ T cell dysfunction in colorectal cancer, co-targeting TIGIT and PD-1 can lead to an effective antitumor response and may serve as a novel therapeutic strategy for colorectal patients.
    Keywords:  CD3+ T cell; TIGIT; colorectal cancer; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2021.688961
  7. Cells. 2021 Oct 05. pii: 2655. [Epub ahead of print]10(10):
    Regulation of T Cells in Cancer by Nitric Oxide.
    Inesa Navasardyan, Benjamin Bonavida.
      The T cell-mediated immune response is primarily involved in the fight against infectious diseases and cancer and its underlying mechanisms are complex. The anti-tumor T cell response is regulated by various T cell subsets and other cells and tissues in the tumor microenvironment (TME). Various mechanisms are involved in the regulation of these various effector cells. One mechanism is the iNOS/.NO that has been reported to be intimately involved in the regulation and differentiation of the various cells that regulate the anti-tumor CD8 T cells. Both endogenous and exogenous .NO are implicated in this regulation. Importantly, the exposure of T cells to .NO had different effects on the immune response, depending on the .NO concentration and time of exposure. For instance, iNOS in T cells regulates activation-induced cell death and inhibits Treg induction. Effector CD8 T cells exposed to .NO result in the upregulation of death receptors and enhance their anti-tumor cytotoxic activity. .NO-Tregs suppress CD4 Th17 cells and their differentiation. Myeloid-derived suppressor cells (MDSCs) expressing iNOS inhibit T cell functions via .NO and inhibit anti-tumor CD8 T cells. Therefore, both .NO donors and .NO inhibitors are potential therapeutics tailored to specific target cells that regulate the T cell effector anti-tumor response.
    Keywords:  T cell; cancer; immunotherapy; nitric oxide; nitric oxide synthase
    DOI:  https://doi.org/10.3390/cells10102655
  8. Nat Metab. 2021 Oct;3(10): 1327-1341
    Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice.
    Heidi H Pak, Spencer A Haws, Cara L Green, Mikaela Koller, Mitchell T Lavarias, Nicole E Richardson, Shany E Yang, Sabrina N Dumas, Michelle Sonsalla, Lindsey Bray, Michelle Johnson, Stephen Barnes, Victor Darley-Usmar, Jianhua Zhang, Chi-Liang Eric Yen, John M Denu, Dudley W Lamming.
      Calorie restriction (CR) promotes healthy ageing in diverse species. Recently, it has been shown that fasting for a portion of each day has metabolic benefits and promotes lifespan. These findings complicate the interpretation of rodent CR studies, in which animals typically eat only once per day and rapidly consume their food, which collaterally imposes fasting. Here we show that a prolonged fast is necessary for key metabolic, molecular and geroprotective effects of a CR diet. Using a series of feeding regimens, we dissect the effects of calories and fasting, and proceed to demonstrate that fasting alone recapitulates many of the physiological and molecular effects of CR. Our results shed new light on how both when and how much we eat regulate metabolic health and longevity, and demonstrate that daily prolonged fasting, and not solely reduced caloric intake, is likely responsible for the metabolic and geroprotective benefits of a CR diet.
    DOI:  https://doi.org/10.1038/s42255-021-00466-9
  9. Biomolecules. 2021 Oct 07. pii: 1478. [Epub ahead of print]11(10):
    Impact of Selenium on Biomarkers and Clinical Aspects Related to Ageing. A Review.
    Urban Alehagen, Trine B Opstad, Jan Alexander, Anders Larsson, Jan Aaseth.
      Selenium (Se) is an essential dietary trace element that plays an important role in the prevention of inflammation, cardiovascular diseases, infections, and cancer. Selenoproteins contain selenocysteine in the active center and include, i.a., the enzymes thioredoxin reductases (TXNRD1-3), glutathione peroxidases (GPX1-4 and GPX6) and methionine sulfoxide reductase, involved in immune functions, metabolic homeostasis, and antioxidant defense. Ageing is an inevitable process, which, i.a., involves an imbalance between antioxidative defense and reactive oxygen species (ROS), changes in protein and mitochondrial renewal, telomere attrition, cellular senescence, epigenetic alterations, and stem cell exhaustion. These conditions are associated with mild to moderate inflammation, which always accompanies the process of ageing and age-related diseases. In older individuals, Se, by being a component in protective enzymes, operates by decreasing ROS-mediated inflammation, removing misfolded proteins, decreasing DNA damage, and promoting telomere length. Se-dependent GPX1-4 and TXNRD1-3 directly suppress oxidative stress. Selenoprotein H in the cell nucleus protects DNA, and selenoproteins residing in the endoplasmic reticulum (ER) assist in the removal of misfolded proteins and protection against ER stress. In this review, we highlight the role of adequate Se status for human ageing and prevention of age-related diseases, and further its proposed role in preservation of telomere length in middle-aged and elderly individuals.
    Keywords:  ageing; cancer; cardiovascular; selenium; sirtuins; telomeres
    DOI:  https://doi.org/10.3390/biom11101478
  10. Cells. 2021 Oct 16. pii: 2775. [Epub ahead of print]10(10):
    Mitochondrial Phospholipid Homeostasis Is Regulated by the i-AAA Protease PaIAP and Affects Organismic Aging.
    Timo Löser, Aljoscha Joppe, Andrea Hamann, Heinz D Osiewacz.
      Mitochondria are ubiquitous organelles of eukaryotic organisms with a number of essential functions, including synthesis of iron-sulfur clusters, amino acids, lipids, and adenosine triphosphate (ATP). During aging of the fungal aging model Podospora anserina, the inner mitochondrial membrane (IMM) undergoes prominent morphological alterations, ultimately resulting in functional impairments. Since phospholipids (PLs) are key components of biological membranes, maintenance of membrane plasticity and integrity via regulation of PL biosynthesis is indispensable. Here, we report results from a lipidomic analysis of isolated mitochondria from P. anserina that revealed an age-related reorganization of the mitochondrial PL profile and the involvement of the i-AAA protease PaIAP in proteolytic regulation of PL metabolism. The absence of PaIAP enhances biosynthesis of characteristic mitochondrial PLs, leads to significant alterations in the acyl composition of the mitochondrial signature PL cardiolipin (CL), and induces mitophagy. These alterations presumably cause the lifespan increase of the PaIap deletion mutant under standard growth conditions. However, PaIAP is required at elevated temperatures and for degradation of superfluous CL synthase PaCRD1 during glycolytic growth. Overall, our study uncovers a prominent role of PaIAP in the regulation of PL homeostasis in order to adapt membrane plasticity to fluctuating environmental conditions as they occur in nature.
    Keywords:  P. anserina; PaCRD1; PaIAP; aging; lipid metabolism; mitochondria
    DOI:  https://doi.org/10.3390/cells10102775
  11. Nat Immunol. 2021 Oct 22.
    Mitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology.
    Hideaki Fujiwara, Keisuke Seike, Michael D Brooks, Anna V Mathew, Ilya Kovalenko, Anupama Pal, Ho-Joon Lee, Daniel Peltier, Stephanie Kim, Chen Liu, Katherine Oravecz-Wilson, Lu Li, Yaping Sun, Jaeman Byun, Yoshinobu Maeda, Max S Wicha, Thomas L Saunders, Alnawaz Rehemtulla, Costas A Lyssiotis, Subramaniam Pennathur, Pavan Reddy.
      Intestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease, inflammatory bowel disease and immune checkpoint blockade-mediated colitis. But little is known about the target cell-intrinsic features that affect disease severity. Here we identified disruption of oxidative phosphorylation and an increase in succinate levels in the IECs from several distinct in vivo models of T cell-mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses, identified disruption of IEC-intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations. The relevance of IEC-intrinsic SDHA in mediating disease severity was confirmed by complementary chemical and genetic experimental approaches and validated in human clinical samples. These data identify a critical role for the alteration of the IEC-specific mitochondrial complex II component SDHA in the regulation of the severity of T cell-mediated intestinal diseases.
    DOI:  https://doi.org/10.1038/s41590-021-01048-3
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