bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022–11–06
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Pleiotropic effects of antibiotics on T cell metabolism and T cell-mediated immunity.
  2. Spermidine Supplementation Enhances Immune Checkpoint Blockade Response.
  3. New insights into the metabolism of Th17 cells.
  4. Cutting Edge: mTORC2 Regulates CD8+ Effector and Memory T Cell Differentiation through Serum and Glucocorticoid Kinase 1.
  5. Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
  6. Immune mobilising T cell receptors redirect polyclonal CD8+ T cells in chronic HIV infection to form immunological synapses.
  7. Endogenous SOD2 (Superoxide Dismutase) Regulates Platelet-Dependent Thrombin Generation and Thrombosis During Aging.
  8. CD103 fate mapping reveals that intestinal CD103- tissue-resident memory T cells are the primary responders to secondary infection.
  9. Adipose tissue macrophages exert systemic metabolic control by manipulating local iron concentrations.
  10. Metabolic requirements of Th17 cells and of B cells: Regulation and defects in health and in inflammatory diseases.
  11. CD8+ T cell differentiation status correlates with the feasibility of sustained unresponsiveness following oral immunotherapy.
  12. Metabolic and physical function are improved with lifelong 15% calorie restriction in aging male mice.
  13. Lactic acid and lactate: revisiting the physiological roles in the tumor microenvironment.
  1. Front Microbiol. 2022 ;13 975436
    Pleiotropic effects of antibiotics on T cell metabolism and T cell-mediated immunity.
    Tobias Franz, Jonas Negele, Philipp Bruno, Martin Böttcher, Marisa Mitchell-Flack, Lea Reemts, Anna Krone, Dimitrios Mougiakakos, Andreas J Müller, Andreas E Zautner, Sascha Kahlfuss.
      T cells orchestrate adaptive and innate immune responses against pathogens and transformed cells. However, T cells are also the main adaptive effector cells that mediate allergic and autoimmune reactions. Within the last few years, it has become abundantly clear that activation, differentiation, effector function, and environmental adaptation of T cells is closely linked to their energy metabolism. Beyond the provision of energy equivalents, metabolic pathways in T cells generate building blocks required for clonal expansion. Furthermore, metabolic intermediates directly serve as a source for epigenetic gene regulation by histone and DNA modification mechanisms. To date, several antibiotics were demonstrated to modulate the metabolism of T cells especially by altering mitochondrial function. Here, we set out to systematically review current evidence about how beta-lactam antibiotics, macrolides, fluoroquinolones, tetracyclines, oxazolidinones, nitroimidazoles, and amphenicols alter the metabolism and effector functions of CD4+ T helper cell populations and CD8+ T cells in vitro and in vivo. Based on this evidence, we have developed an overview on how the use of these antibiotics may be beneficial or detrimental in T cell-mediated physiological and pathogenic immune responses, such as allergic and autoimmune diseases, by altering the metabolism of different T cell populations.
    Keywords:  T cells; antibiotics; bacteria; host-pathogen; metabolism; mitochondria
    DOI:  https://doi.org/10.3389/fmicb.2022.975436
  2. Cancer Discov. 2022 Nov 04. OF1
    Spermidine Supplementation Enhances Immune Checkpoint Blockade Response.
      Spermidine enhances T-cell mitochondrial metabolism and the antitumor response to anti-PD-L1.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-196
  3. Immunol Med. 2022 Nov 03. 1-10
    New insights into the metabolism of Th17 cells.
    Michihito Kono.
      T helper 17 (Th17) cells are IL-17-producing CD4 T cells that play a crucial role in autoimmune diseases. IL-17 is a key cytokine for host protection against mucosal and skin infection but is also one of the major pathogenic cytokines. IL-1 and IL-23 are requisite for stimulating pathogenic Th17 cell differentiation and proliferation. Therapeutics targeting the IL-17/IL-23 pathway are widely used clinically for the treatment of autoimmune diseases. Besides IL-17, pathogenic Th17 cells produce granulocyte-macrophage colony-stimulating factor, tumor necrosis factor α, interferon γ, IL-21 and IL-22. However, Th17-targeted therapy has not yet been established. T cell metabolism orchestrates T cell survival, cell differentiation, epigenetic change and function and each T cell subset favors a particular metabolic pathway. Recent studies have provided novel insights into the role of T cell metabolism in the pathogenesis of autoimmune diseases. The current review focuses on the role of Th17 cell metabolism in autoimmune diseases, particularly glycolysis, amino acid metabolism, lipid metabolism, as well as the regulators of these processes, including mTORC1. Therapeutics targeting T cell metabolism in autoimmune diseases could serve as a possible treatment option for patients who are refractory to or unresponsive to conventional therapy.
    Keywords:  Cellular metabolism; IL-17; Th17; glutaminolysis; glycolysis
    DOI:  https://doi.org/10.1080/25785826.2022.2140503
  4. J Immunol. 2022 Nov 04. pii: ji2100669. [Epub ahead of print]
    Cutting Edge: mTORC2 Regulates CD8+ Effector and Memory T Cell Differentiation through Serum and Glucocorticoid Kinase 1.
    Chirag H Patel, Emily B Heikamp, Wei Xu, Im-Hong Sun, Min-Hee Oh, Im-Meng Sun, Jiayu Wen, Ada J Tam, Richard L Blosser, Jonathan D Powell.
      The mechanistic target of rapamycin is an essential regulator of T cell metabolism and differentiation. In this study, we demonstrate that serum- and glucocorticoid-regulated kinase 1 (SGK1), a downstream node of mechanistic target of rapamycin complex 2 signaling, represses memory CD8+ T cell differentiation. During acute infections, murine SGK1-deficient CD8+ T cells adopt an early memory precursor phenotype leading to more long-lived memory T cells. Thus, SGK1-deficient CD8+ T cells demonstrate an enhanced recall capacity in response to reinfection and can readily reject tumors. Mechanistically, activation of SGK1-deficient CD8+ T cells results in decreased Foxo1 phosphorylation and increased nuclear translocation of Foxo1 to promote early memory development. Overall, SGK1 might prove to be a powerful target for enhancing the efficacy of vaccines and tumor immunotherapy.
    DOI:  https://doi.org/10.4049/jimmunol.2100669
  5. Mol Cell. 2022 Oct 31. pii: S1097-2765(22)00962-5. [Epub ahead of print]
    Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
    Patricia Altea-Manzano, Anke Vandekeere, Joy Edwards-Hicks, Mar Roldan, Emily Abraham, Xhordi Lleshi, Ania Naila Guerrieri, Domenica Berardi, Jimi Wills, Jair Marques Junior, Asimina Pantazi, Juan Carlos Acosta, Rosario M Sanchez-Martin, Sarah-Maria Fendt, Miguel Martin-Hernandez, Andrew J Finch.
      Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD+, resulting in cessation of the oxidative tricarboxylic acid (TCA) cycle and a consequent dependence upon reductive carboxylation for aspartate synthesis. NAD+ regeneration alone in the cytosol can rescue the viability of ETC-deficient cells. Yet, how this occurs and whether transfer of oxidative equivalents to the mitochondrion is required remain unknown. Here, we show that inhibition of the ETC drives reversal of the mitochondrial aspartate transaminase (GOT2) as well as malate and succinate dehydrogenases (MDH2 and SDH) to transfer oxidative NAD+ equivalents into the mitochondrion. This supports the NAD+-dependent activity of the mitochondrial glutamate dehydrogenase (GDH) and thereby enables anaplerosis-the entry of glutamine-derived carbon into the TCA cycle and connected biosynthetic pathways. Thus, under impaired ETC function, the cytosolic redox state is communicated into the mitochondrion and acts as a rheostat to support GDH activity and cell viability.
    Keywords:  anaplerosis; cancer; cancer metabolism; metabolism; mitochondrion; redox; redox transfer; respiration
    DOI:  https://doi.org/10.1016/j.molcel.2022.10.005
  6. Sci Rep. 2022 Nov 01. 12(1): 18366
    Immune mobilising T cell receptors redirect polyclonal CD8+ T cells in chronic HIV infection to form immunological synapses.
    Zoë Wallace, Jakub Kopycinski, Hongbing Yang, Michelle L McCully, Christian Eggeling, Jakub Chojnacki, Lucy Dorrell.
      T cell exhaustion develops in human immunodeficiency virus (HIV) infection due to chronic viral antigenic stimulation. This adaptive response primarily affects virus-specific CD8+ T cells, which may remain dysfunctional despite viral load-reducing antiretroviral therapy; however, abnormalities may also be evident in non-HIV-specific populations. Both could limit the efficacy of cell therapies against viral reservoirs. Here, we show that bulk (polyclonal) CD8+ T cells from people living with HIV (PLWH) express proposed markers of dysfunctional HIV-specific T cells at high levels yet form lytic immunological synapses (IS) and eliminate primary resting infected (HIV Gaglo) CD4+ T cells, when redirected by potent bispecific T cell-retargeting molecules, Immune mobilising monoclonal T cell receptors (TCR) Against Virus (ImmTAV). While PLWH CD8+ T cells are functionally impaired when compared to CD8+ T cells from HIV-naïve donors, ImmTAV redirection enables them to eliminate Gaglo CD4+ T cells that are insensitive to autologous HIV-specific cytolytic T cells. ImmTAV molecules may therefore be able to target HIV reservoirs, which represent a major barrier to a cure.
    DOI:  https://doi.org/10.1038/s41598-022-23228-3
  7. Arterioscler Thromb Vasc Biol. 2022 Nov 03.
    Endogenous SOD2 (Superoxide Dismutase) Regulates Platelet-Dependent Thrombin Generation and Thrombosis During Aging.
    Vijay K Sonkar, Alicia S Eustes, Azaj Ahmed, Melissa Jensen, Mitali V Solanki, Jagadish Swamy, Rahul Kumar, Trevor P Fidler, Jon C D Houtman, Bryan G Allen, Douglas R Spitz, E Dale Abel, Sanjana Dayal.
       BACKGROUND: Reactive oxygen species (ROS) contribute to platelet hyperactivation during aging. Several oxidative pathways and antioxidant enzymes have been implicated; however, their mechanistic contributions during aging remain elusive. We hypothesized that mitochondria are an important source of platelet ROS and that mitochondrial SOD2 (superoxide dismutase) protects against mitochondrial ROS-driven platelet activation and thrombosis during aging.
    METHODS: We studied littermates of platelet-specific SOD2-knockout (SOD2fl/flPf4Cre, pSOD2-KO) and control (SOD2fl/fl) mice at young (4-5 months) or old (18-20 months) ages. We examined agonist-induced platelet activation, platelet-dependent thrombin generation potential, and susceptibility to in vivo thrombosis.
    RESULTS: Platelet αIIbβ3 activation, aggregation, and adhesion were increased to similar extents in aged mice of both genotypes compared with young mice. In contrast, the age-dependent increases in mitochondrial and total cellular ROS, calcium elevation, and phosphatidylserine exposure were augmented in platelets from pSOD2-KO mice compared with control mice. Aged pSOD2-KO mice showed increased platelet-dependent thrombin generation compared with aged control mice. In vivo, aged pSOD2-KO mice exhibited enhanced susceptibility to carotid artery and pulmonary thrombosis compared to aged control mice. Adoptive transfer of platelets from aged pSOD2-KO but not aged control mice increased thrombotic susceptibility in aged host mice, suggesting a prothrombotic effect of platelet pSOD2 deficiency. Treatment with avasopasem manganese (GC4419), a SOD mimetic, decreased platelet mitochondrial pro-oxidants, cellular ROS levels, and inhibited procoagulant platelet formation and arterial thrombosis in aged mice.
    CONCLUSIONS: Platelet mitochondrial ROS contributes to age-related thrombosis and endogenous SOD2 protects from platelet-dependent thrombin generation and thrombosis during aging.
    Keywords:  aging; genotype; mice; mitochondria; thrombin
    DOI:  https://doi.org/10.1161/ATVBAHA.121.317735
  8. Sci Immunol. 2022 Nov 11. 7(77): eabl9925
    CD103 fate mapping reveals that intestinal CD103- tissue-resident memory T cells are the primary responders to secondary infection.
    Helen Y Fung, Matthew Teryek, Alexander D Lemenze, Tessa Bergsbaken.
      Tissue-resident memory T (TRM) cells remain poised in the tissue and mediate robust protection from secondary infection. TRM cells within the intestine and other tissues are heterogeneous in their phenotype and function; however, the contributions of these TRM subsets to secondary infection remain poorly defined. To address the plasticity of intestinal TRM subsets and their role in local and systemic immunity, we generated mice to fate map intestinal CD103+ TRM cells and track their location and function during secondary infection with Yersinia pseudotuberculosis. We found that CD103+ TRM cells remained lodged in the tissue and were poorly reactivated during secondary challenge. CD103- TRM cells were the primary responders to secondary infection and expanded within the tissue, with limited contribution from circulating memory T cells. The transcriptional profile of CD103- TRM cells demonstrated maintenance of a gene signature similar to circulating T cells along with increased cytokine production and migratory potential. CD103- TRM cells also expressed genes associated with T cell receptor (TCR) activation and displayed enhanced TCR-mediated reactivation both in vitro and in vivo compared with their CD103+ counterparts. These studies reveal the limited recall potential of CD103+ TRM subsets and the role of CD103- TRM cells as central memory-like T cells within peripheral tissues.
    DOI:  https://doi.org/10.1126/sciimmunol.abl9925
  9. Nat Metab. 2022 Nov 03.
    Adipose tissue macrophages exert systemic metabolic control by manipulating local iron concentrations.
    Nolwenn Joffin, Christy M Gliniak, Jan-Bernd Funcke, Vivian A Paschoal, Clair Crewe, Shiuhwei Chen, Ruth Gordillo, Christine M Kusminski, Da Young Oh, Werner J Geldenhuys, Philipp E Scherer.
      Iron is essential to many fundamental biological processes, but its cellular compartmentalization and concentration must be tightly controlled. Although iron overload can contribute to obesity-associated metabolic deterioration, the subcellular localization and accumulation of iron in adipose tissue macrophages is largely unknown. Here, we show that macrophage mitochondrial iron levels control systemic metabolism in male mice by altering adipocyte iron concentrations. Using various transgenic mouse models to manipulate the macrophage mitochondrial matrix iron content in an inducible fashion, we demonstrate that lowering macrophage mitochondrial matrix iron increases numbers of M2-like macrophages in adipose tissue, lowers iron levels in adipocytes, attenuates inflammation and protects from high-fat-diet-induced metabolic deterioration. Conversely, elevating macrophage mitochondrial matrix iron increases M1-like macrophages and iron levels in adipocytes, exacerbates inflammation and worsens high-fat-diet-induced metabolic dysfunction. These phenotypes are robustly reproduced by transplantation of a small amount of fat from transgenic to wild-type mice. Taken together, we identify macrophage mitochondrial iron levels as a crucial determinant of systemic metabolic homeostasis in mice.
    DOI:  https://doi.org/10.1038/s42255-022-00664-z
  10. Front Immunol. 2022 ;13 990794
    Metabolic requirements of Th17 cells and of B cells: Regulation and defects in health and in inflammatory diseases.
    Jonas Bystrom, Taher E Taher, Sian M Henson, David J Gould, Rizgar A Mageed.
      The immune system protects from infections and cancer through complex cellular networks. For this purpose, immune cells require well-developed mechanisms of energy generation. However, the immune system itself can also cause diseases when defective regulation results in the emergence of autoreactive lymphocytes. Recent studies provide insights into how differential patterns of immune cell responses are associated with selective metabolic pathways. This review will examine the changing metabolic requirements of Th17 cells and of B cells at different stages of their development and activation. Both cells provide protection but can also mediate diseases through the production of autoantibodies and the production of proinflammatory mediators. In health, B cells produce antibodies and cytokines and present antigens to T cells to mount specific immunity. Th17 cells, on the other hand, provide protection against extra cellular pathogens at mucosal surfaces but can also drive chronic inflammation. The latter cells can also promote the differentiation of B cells to plasma cells to produce more autoantibodies. Metabolism-regulated checkpoints at different stages of their development ensure the that self-reactive B cells clones and needless production of interleukin (IL-)17 are limited. The metabolic regulation of the two cell types has some similarities, e.g. the utility of hypoxia induced factor (HIF)1α during low oxygen tension, to prevent autoimmunity and regulate inflammation. There are also clear differences, as Th17 cells only are vulnerable to the lack of certain amino acids. B cells, unlike Th17 cells, are also dependent of mechanistic target of rapamycin 2 (mTORC2) to function. Significant knowledge has recently been gained, particularly on Th17 cells, on how metabolism regulates these cells through influencing their epigenome. Metabolic dysregulation of Th17 cells and B cells can lead to chronic inflammation. Disease associated alterations in the genome can, in addition, cause dysregulation to metabolism and, thereby, result in epigenetic alterations in these cells. Recent studies highlight how pathology can result from the cooperation between the two cell types but only few have so far addressed the key metabolic alterations in such settings. Knowledge of the impact of metabolic dysfunction on chronic inflammation and pathology can reveal novel therapeutic targets to treat such diseases.
    Keywords:  B cells; OXPHOS; Th17 cells; autoimmunity; epigenetics; mTORC; metabolism
    DOI:  https://doi.org/10.3389/fimmu.2022.990794
  11. Nat Commun. 2022 Nov 04. 13(1): 6646
    CD8+ T cell differentiation status correlates with the feasibility of sustained unresponsiveness following oral immunotherapy.
    Abhinav Kaushik, Diane Dunham, Xiaorui Han, Evan Do, Sandra Andorf, Sheena Gupta, Andrea Fernandes, Laurie Elizabeth Kost, Sayantani B Sindher, Wong Yu, Mindy Tsai, Robert Tibshirani, Scott D Boyd, Manisha Desai, Holden T Maecker, Stephen J Galli, R Sharon Chinthrajah, Rosemarie H DeKruyff, Monali Manohar, Kari C Nadeau.
      While food allergy oral immunotherapy (OIT) can provide safe and effective desensitization (DS), the immune mechanisms underlying development of sustained unresponsiveness (SU) following a period of avoidance are largely unknown. Here, we compare high dimensional phenotypes of innate and adaptive immune cell subsets of participants in a previously reported, phase 2 randomized, controlled, peanut OIT trial who achieved SU vs. DS (no vs. with allergic reactions upon food challenge after a withdrawal period; n = 21 vs. 30 respectively among total 120 intent-to-treat participants). Lower frequencies of naïve CD8+ T cells and terminally differentiated CD57+CD8+ T cell subsets at baseline (pre-OIT) are associated with SU. Frequency of naïve CD8+ T cells shows a significant positive correlation with peanut-specific and Ara h 2-specific IgE levels at baseline. Higher frequencies of IL-4+ and IFNγ+ CD4+ T cells post-OIT are negatively correlated with SU. Our findings provide evidence that an immune signature consisting of certain CD8+ T cell subset frequencies is potentially predictive of SU following OIT.
    DOI:  https://doi.org/10.1038/s41467-022-34222-8
  12. Biogerontology. 2022 Oct 31.
    Metabolic and physical function are improved with lifelong 15% calorie restriction in aging male mice.
    Emily C Peters, Luke Safayan, Tyler J Marx, Emily Ngu, Anastasiia Vasileva, India Zappia, William H Powell, Frank A Duca, Jennifer H Stern.
      Chronic calorie restriction (CR) results in lengthened lifespan and reduced disease risk. Many previous studies have implemented 30-40% calorie restriction to investigate these benefits. The goal of our study was to investigate the effects of calorie restriction, beginning at 4 months of age, on metabolic and physical changes induced by aging. Male C57BL/6NCrl calorie restricted and ad libitum fed control mice were obtained from the National Institute on Aging (NIA) and studied at 10, 18, 26, and 28 months of age to better understand the metabolic changes that occur in response to CR in middle age and advanced age. Food intake was measured in ad libitum fed controls to assess the true degree of CR (15%) in these mice. We found that 15% CR decreased body mass and liver triglyceride content, improved oral glucose clearance, and increased all limb grip strength in 10- and 18-month-old mice. Glucose clearance in ad libitum fed 26- and 28-month-old mice is enhanced relative to younger mice but was not further improved by CR. CR decreased basal insulin concentrations in all age groups and improved insulin sensitivity and rotarod time to fall in 28-month-old mice. The results of our study demonstrate that even a modest reduction (15%) in caloric intake may improve metabolic and physical health. Thus, moderate calorie restriction may be a dietary intervention to promote healthy aging with improved likelihood for adherence in human populations.
    Keywords:  Calorie restriction; Glucose homeostasis; Healthspan; Insulin sensitivity; Liver fat
    DOI:  https://doi.org/10.1007/s10522-022-09996-5
  13. Trends Immunol. 2022 Oct 29. pii: S1471-4906(22)00213-7. [Epub ahead of print]
    Lactic acid and lactate: revisiting the physiological roles in the tumor microenvironment.
    Petya Apostolova, Erika L Pearce.
      Lactic acid production has been regarded as a mechanism by which malignant cells escape immunosurveillance. Recent technological advances in mass spectrometry and the use of cell culture media with a physiological nutrient composition have shed new light on the role of lactic acid and its conjugate lactate in the tumor microenvironment. Here, we review novel work identifying lactate as a physiological carbon source for mammalian tumors and immune cells. We highlight evidence that its use as a substrate is distinct from the immunosuppressive acidification of the extracellular milieu by lactic acid protons. Together, data suggest that neutralizing the effects of intratumoral acidity while maintaining physiological lactate metabolism in cytotoxic CD8+ T cells should be pursued to boost anti-tumor immunity.
    DOI:  https://doi.org/10.1016/j.it.2022.10.005
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