bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022‒04‒10
twelve papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research
  1. The Role of Autophagy in the Function of CD4+ T Cells and the Development of Chronic Inflammatory Diseases.
  2. High Levels of CD244 Rather Than CD160 Associate With CD8+ T-Cell Aging.
  3. Sugar addiction: An Achilles' heel of auto-immune diseases?
  4. Mitochondrial Mass of Naïve T Cells Is Associated with Aerobic Fitness and Energy Expenditure of Active and Inactive Adults.
  5. Metformin treatment rescues CD8+ T cell response to immune checkpoint inhibitor therapy in mice with NAFLD.
  6. Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling.
  7. Glutathione-dependent redox balance characterizes the distinct metabolic properties of follicular and marginal zone B cells.
  8. Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control.
  9. Drug delivery for metabolism targeted cancer immunotherapy.
  10. Compartmentalized metabolism supports midgestation mammalian development.
  11. Metformin ameliorates thymus degeneration of mice by regulating mitochondrial function.
  12. Gut microbiota severely hampers the efficacy of NAD-lowering therapy in leukemia.
  1. Front Pharmacol. 2022 ;13 860146
    The Role of Autophagy in the Function of CD4+ T Cells and the Development of Chronic Inflammatory Diseases.
    Jiung Jeong, Young Joon Choi, Heung Kyu Lee.
      Uncontrolled acute inflammation progresses to persistent inflammation that leads to various chronic inflammatory diseases, including asthma, Crohn's disease, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus. CD4+ T cells are key immune cells that determine the development of these chronic inflammatory diseases. CD4+ T cells orchestrate adaptive immune responses by producing cytokines and effector molecules. These functional roles of T cells vary depending on the surrounding inflammatory or anatomical environment. Autophagy is an important process that can regulate the function of CD4+ T cells. By lysosomal degradation of cytoplasmic materials, autophagy mediates CD4+ T cell-mediated immune responses, including cytokine production, proliferation, and differentiation. Furthermore, through canonical processes involving autophagy machinery, autophagy also contributes to the development of chronic inflammatory diseases. Therefore, a targeted intervention of autophagy processes could be used to treat chronic inflammatory diseases. This review focuses on the role of autophagy via CD4+ T cells in the pathogenesis and treatment of such diseases. In particular, we explore the underlying mechanisms of autophagy in the regulation of CD4+ T cell metabolism, survival, development, proliferation, differentiation, and aging. Furthermore, we suggest that autophagy-mediated modulation of CD4+ T cells is a promising therapeutic target for treating chronic inflammatory diseases.
    Keywords:  CD4+ T cell; Crohn’s disease; asthma; autophagy; multiple sclerosis; rheumatoid arthritis; systemic lupus erythematosus
    DOI:  https://doi.org/10.3389/fphar.2022.860146
  2. Front Immunol. 2022 ;13 853522
    High Levels of CD244 Rather Than CD160 Associate With CD8+ T-Cell Aging.
    Xinyue Wang, Di Wang, Juan Du, Yuqing Wei, Rui Song, Beibei Wang, Shuang Qiu, Bei Li, Leidan Zhang, Yongqin Zeng, Hongxin Zhao, Yaxian Kong.
      Aging leads to functional dysregulation of the immune system, especially T cell defects. Previous studies have shown that the accumulation of co-inhibitory molecules plays an essential role in both T cell exhaustion and aging. In the present study, we showed that CD244 and CD160 were both up-regulated on CD8+ T cells of elderly individuals. CD244+CD160- CD8+ T cells displayed the increased activity of β-GAL, higher production of cytokines, and severe metabolic disorders, which were characteristics of immune aging. Notably, the functional dysregulation associated with aging was reversed by blocking CD244 instead of CD160. Meanwhile, CD244+CD160+ CD8+ T cells exhibited features of exhaustion, including lower levels of cytokine, impaired proliferation, and intrinsic transcriptional regulation, compared to CD244+CD160- population. Collectively, our findings demonstrated that CD244 rather than CD160 acts as a prominent regulator involved in T cell aging, providing a solid therapeutic target to improve disorders and comorbidities correlated to immune system aging.
    Keywords:  CD160; CD244; CD8+ T cells; aging; immune aging
    DOI:  https://doi.org/10.3389/fimmu.2022.853522
  3. Cell Metab. 2022 Apr 05. pii: S1550-4131(22)00095-X. [Epub ahead of print]34(4): 503-505
    Sugar addiction: An Achilles' heel of auto-immune diseases?
    Dietmar M W Zaiss, Paul J Coffer.
      In this issue of Cell Metabolism, Hochrein et al. identify a metabolic checkpoint controlling the transcriptional programming of effector CD4+ T cells. The authors show that GLUT3-mediated glucose import and ACLY-dependent acetyl-CoA generation control histone acetylation and, hence, the epigenetic imprinting of effector gene expression in differentiated effector CD4+ T cells. These findings suggest a novel therapeutic target for inflammation-associated diseases.
    DOI:  https://doi.org/10.1016/j.cmet.2022.03.007
  4. Med Sci Sports Exerc. 2022 Apr 01.
    Mitochondrial Mass of Naïve T Cells Is Associated with Aerobic Fitness and Energy Expenditure of Active and Inactive Adults.
    Jessica R Alley, Rudy J Valentine, Marian L Kohut.
      PURPOSE: Chronic exercise training is known to induce metabolic changes, but whether these adaptations extend to lymphocytes and how this may impact immune function remains largely unknown. This study was conducted to determine the extent to which mitochondrial characteristics of naïve T cells differ according to fitness status and to further examine energy production pathways of cells from aerobically trained and inactive participants.METHODS: Blood was collected from 30 aerobically active (>six hours per week) or inactive (<90 min per week) men and women. Naïve T cell mitochondrial mass, membrane potential, and biogenesis were assessed with flow cytometry. Participants completed a treadmill maximal oxygen consumption (VO2peak) test and wore a physical activity monitor for one week. In a subset of participants, naïve CD8+ T cell activation-induced glycolytic and mitochondrial ATP production was measured.
    RESULTS: Active participants exhibited 16.7% more naïve CD8+ T cell mitochondrial mass (p = 0.046), 34% greater daily energy expenditure (p < 0.001), and 39.6% higher relative VO2peak (p < 0.001), along with 33.9% lower relative body fatness (p < 0.001). Among all participants, naïve CD8+ T cell mitochondrial mass was correlated with estimated energy expenditure (r = 0.36, p = 0.048) and VO2peak (r = 0.47, p = 0.009). There were no significant differences in ATP production, mitochondrial biogenesis, or mitochondrial membrane potential between active and inactive groups.
    CONCLUSIONS: This is the first study to examine the effects of aerobic exercise training status on metabolic parameters within human naïve T cells. Findings suggest that mitochondrial adaptations in certain immune cell types are positively associated with aerobic fitness and energy expenditure. This study provides a foundation for future development of prophylactic and therapeutic interventions targeting specific immune cell subsets to improve the immune response and overall health.
    DOI:  https://doi.org/10.1249/MSS.0000000000002914
  5. J Hepatol. 2022 Apr 01. pii: S0168-8278(22)00178-7. [Epub ahead of print]
    Metformin treatment rescues CD8+ T cell response to immune checkpoint inhibitor therapy in mice with NAFLD.
    Simon Wabitsch, Justin D McCallen, Olena Kamenyeva, Benjamin Ruf, John C McVey, Juraj Kabat, Juliane S Walz, Yaron Rotman, Kylynda C Bauer, Amanda J Craig, Marie Pouzolles, Ira Phadke, Vanessa Catania, Benjamin L Green, Claude Fu, Laurence P Diggs, Bernd Heinrich, Xin Wei Wang, Chi Ma, Tim F Greten.
      BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) represents the fastest growing underlying cause of hepatocellular carcinoma (HCC) and has been shown to impact immune effector cell function. The standard of care for the treatment of advanced HCC is immune checkpoint inhibitor (ICI) therapy, yet NASH may negatively affect the efficacy of ICI therapy in HCC. The immunologic mechanisms underlying the impact of NASH on ICI therapy remain unclear.METHODS: Here, using multiple murine NASH models, we analyzed the influence of NASH on the CD8+ T cell-dependent anti-PD-1 responses against liver cancer. We characterized CD8+ T cells' transcriptomic, functional, and motility changes in normal (ND) and NASH diet.
    RESULTS: NASH blunted the effect of anti-PD-1 therapy against liver cancers in multiple murine models. NASH caused a proinflammatory phenotypic change of hepatic CD8+ T cells. Transcriptomic analysis revealed changes related to NASH-dependent impairment of hepatic CD8+ T cell metabolism. In vivo imaging analysis showed reduced motility of intra-tumoral CD8+ T cells. Metformin treatment rescued the efficacy of anti-PD-1 therapy against liver tumors in NASH.
    CONCLUSIONS: Our study discovered a critical regulation of CD8+ T cell metabolism in ICI therapy for liver cancer in the context of NASH, a finding with potential implications for treating liver cancer patients with NASH.
    LAY SUMMARY: Non-alcoholic fatty liver disease impairs motility, metabolic function and response to anti-PD-1 treatment of hepatic CD8+ T cells, which can be rescued by metformin treatment.
    Keywords:  NASH immunology; hepatic intravital imaging; hepatic transcriptomics; immunometabolism; liver cancer; metabolic syndrome
    DOI:  https://doi.org/10.1016/j.jhep.2022.03.010
  6. Nat Commun. 2022 Apr 08. 13(1): 1923
    Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling.
    Georgi Apriamashvili, David W Vredevoogd, Oscar Krijgsman, Onno B Bleijerveld, Maarten A Ligtenberg, Beaunelle de Bruijn, Julia Boshuizen, Joleen J H Traets, Daniela D'Empaire Altimari, Alex van Vliet, Chun-Pu Lin, Nils L Visser, James D Londino, Rebekah Sanchez-Hodge, Leah E Oswalt, Selin Altinok, Jonathan C Schisler, Maarten Altelaar, Daniel S Peeper.
      The cytokine IFNγ differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about regulation of its receptor (IFNγ-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFNγ-R1 cell surface abundance, we identify STUB1 as an E3 ubiquitin ligase for IFNγ-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFNγ-R1/JAK1 complex through IFNγ-R1K285 and JAK1K249. Conversely, STUB1 inactivation amplifies IFNγ signaling, sensitizing tumor cells to cytotoxic T cells in vitro. This is corroborated by an anticorrelation between STUB1 expression and IFNγ response in ICB-treated patients. Consistent with the context-dependent effects of IFNγ in vivo, anti-PD-1 response is increased in heterogenous tumors comprising both wildtype and STUB1-deficient cells, but not full STUB1 knockout tumors. These results uncover STUB1 as a critical regulator of IFNγ-R1, and highlight the context-dependency of STUB1-regulated IFNγ signaling for ICB outcome.
    DOI:  https://doi.org/10.1038/s41467-022-29442-x
  7. Nat Commun. 2022 Apr 04. 13(1): 1789
    Glutathione-dependent redox balance characterizes the distinct metabolic properties of follicular and marginal zone B cells.
    Davide G Franchina, Henry Kurniawan, Melanie Grusdat, Carole Binsfeld, Luana Guerra, Lynn Bonetti, Leticia Soriano-Baguet, Anouk Ewen, Takumi Kobayashi, Sophie Farinelle, Anna Rita Minafra, Niels Vandamme, Anaïs Carpentier, Felix K Borgmann, Christian Jäger, Ying Chen, Markus Kleinewietfeld, Vasilis Vasiliou, Michel Mittelbronn, Karsten Hiller, Philipp A Lang, Dirk Brenner.
      The metabolic principles underlying the differences between follicular and marginal zone B cells (FoB and MZB, respectively) are not well understood. Here we show, by studying mice with B cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that glutathione synthesis affects homeostasis and differentiation of MZB to a larger extent than FoB, while glutathione-dependent redox control contributes to the metabolic dependencies of FoB. Specifically, Gclc ablation in FoB induces metabolic features of wild-type MZB such as increased ATP levels, glucose metabolism, mTOR activation, and protein synthesis. Furthermore, Gclc-deficient FoB have a block in the mitochondrial electron transport chain (ETC) due to diminished complex I and II activity and thereby accumulate the tricarboxylic acid cycle metabolite succinate. Finally, Gclc deficiency hampers FoB activation and antibody responses in vitro and in vivo, and induces susceptibility to viral infections. Our results thus suggest that Gclc is required to ensure the development of MZB, the mitochondrial ETC integrity in FoB, and the efficacy of antiviral humoral immunity.
    DOI:  https://doi.org/10.1038/s41467-022-29426-x
  8. J Clin Invest. 2022 Apr 05. pii: e157549. [Epub ahead of print]
    Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control.
    Federico Perdomo-Celis, Caroline Passaes, Valérie Monceaux, Stevenn Volant, Faroudy Boufassa, Pierre de Truchis, Morgane Marcou, Katia Bourdic, Laurence Weiss, Corinne Jung, Christine Bourgeois, Cécile Goujard, Laurence Meyer, Michaela Müller-Trutwin, Olivier Lambotte, Asier Sáez-Cirión.
      Virus-specific CD8+ T cells play a central role in HIV-1 natural controllers to maintain suppressed viremia in the absence of antiretroviral therapy. These cells display a memory program that confers them stemness properties, high survival, polyfunctionality, proliferative capacity, metabolic plasticity, and antiviral potential. The development and maintenance of such qualities by memory CD8+ T cells appear crucial to achieving natural HIV-1 control. Here we show that targeting the signaling pathways Wnt/TCF-1 and mTORC through GSK3 inhibition to reprogram HIV-specific CD8+ T cells from non-controllers promoted functional capacities associated with natural control of infection. Features of such reprogrammed cells included the enrichment in TCF-1+ less-differentiated subsets, superior response to antigen, enhanced survival, polyfunctionality, metabolic plasticity, less mTORC1-dependency, improved response to γ-chain cytokines and stronger HIV suppressive capacity. Thus, such CD8+ T cell reprogramming, combined with other available immunomodulators, might represent a promising strategy for adoptive cell therapy in the search for an HIV-1 cure.
    Keywords:  AIDS/HIV; Adaptive immunity; Cellular immune response; Immunology; Immunotherapy
    DOI:  https://doi.org/10.1172/JCI157549
  9. Adv Drug Deliv Rev. 2022 Mar 31. pii: S0169-409X(22)00132-6. [Epub ahead of print]184 114242
    Drug delivery for metabolism targeted cancer immunotherapy.
    Taravat Khodaei, Sahil Inamdar, Abhirami P Suresh, Abhinav P Acharya.
      Drug delivery vehicles have made a great impact on cancer immunotherapies in clinics and pre-clinical research. Notably, the science of delivery of cancer vaccines and immunotherapeutics, modulating immune cell functions has inspired development of several successful companies and clinical products. Interestingly, these drug delivery modalities not only modulate the function of immune cells (often quantified at the mRNA and protein levels), but also modulate the metabolism of these cells. Specifically, cancer immunotherapy often leads to activation of different immune cells such as dendritic cells, macrophages and T cells, which is driven by energy metabolism of these cells. Recently, there has been a great excitement about interventions that can directly modulate the energy metabolism of these immune cells and thus affect their function and in turn lead to a robust cancer immune response. Here we review few strategies that have been tested in clinic and pre-clinical research for generating effective metabolism-associated cancer therapies and immunotherapies.
    Keywords:  Cancer metabolism; Immunometabolism; Immunotherapy; Metabolism targeting
    DOI:  https://doi.org/10.1016/j.addr.2022.114242
  10. Nature. 2022 Apr 06.
    Compartmentalized metabolism supports midgestation mammalian development.
    Ashley Solmonson, Brandon Faubert, Wen Gu, Aparna Rao, Mitzy A Cowdin, Ivan Menendez-Montes, Sherwin Kelekar, Thomas J Rogers, Chunxiao Pan, Gerardo Guevara, Amy Tarangelo, Lauren G Zacharias, Misty S Martin-Sandoval, Duyen Do, Panayotis Pachnis, Dennis Dumesnil, Thomas P Mathews, Alpaslan Tasdogan, An Pham, Ling Cai, Zhiyu Zhao, Min Ni, Ondine Cleaver, Hesham A Sadek, Sean J Morrison, Ralph J DeBerardinis.
      Mammalian embryogenesis requires rapid growth and proper metabolic regulation1. Midgestation features increasing oxygen and nutrient availability concomitant with fetal organ development2,3. Understanding how metabolism supports development requires approaches to observe metabolism directly in model organisms in utero. Here we used isotope tracing and metabolomics to identify evolving metabolic programmes in the placenta and embryo during midgestation in mice. These tissues differ metabolically throughout midgestation, but we pinpointed gestational days (GD) 10.5-11.5 as a transition period for both placenta and embryo. Isotope tracing revealed differences in carbohydrate metabolism between the tissues and rapid glucose-dependent purine synthesis, especially in the embryo. Glucose's contribution to the tricarboxylic acid (TCA) cycle rises throughout midgestation in the embryo but not in the placenta. By GD12.5, compartmentalized metabolic programmes are apparent within the embryo, including different nutrient contributions to the TCA cycle in different organs. To contextualize developmental anomalies associated with Mendelian metabolic defects, we analysed mice deficient in LIPT1, the enzyme that activates 2-ketoacid dehydrogenases related to the TCA cycle4,5. LIPT1 deficiency suppresses TCA cycle metabolism during the GD10.5-GD11.5 transition, perturbs brain, heart and erythrocyte development and leads to embryonic demise by GD11.5. These data document individualized metabolic programmes in developing organs in utero.
    DOI:  https://doi.org/10.1038/s41586-022-04557-9
  11. Int Immunopharmacol. 2022 Apr 05. pii: S1567-5769(22)00228-4. [Epub ahead of print]108 108744
    Metformin ameliorates thymus degeneration of mice by regulating mitochondrial function.
    Shu-Ping Yang, Qing Su, Ya-Ru Zhang, Yun Sun, Yu-Rong Chai.
      As the main lymphoid organ, the thymus degenerates with age. The loss of thymic epithelial cells is mainly related to thymus degeneration and reduced T cells development. As an insulin sensitizer, metformin is a first-line drug for the treatment of diabetes and has been shown to prolong the lifespan of mice, but the mechanism is still unclear. In this study, we explored the therapeutic effect of metformin on thymus degeneration in the accelerated aging mice, which was established by intraperitoneal injection D-galactose (120 mg/kg/day) for eight weeks. Metformin was intragastrically given with 100 or 300 mg/kg body weight per day, respectively, for six weeks. Histological examination showed that metformin administration could alleviate thymus atrophy caused by D-galactose. In addition, metformin therapy increased mitochondrial membrane potential, with a reduction in mitochondrial reactive oxygen species, MDA and SOD levels, and restored mitochondrial balance through enhanced expression of dynamin-related protein 1 (Drp1). Furthermore, metformin altered T lymphocyte subsets and cellular senescent cells; the expression of FoxN1, Aire and Sox2 of thymic epithelial cells also increased. Thus, metformin presented a positive effect on thymic degeneration through improving mitochondrial function. Taken together, these findings revealed an unexpected complexity in the anti-aging of this widely used drug.
    Keywords:  Aging; D-galactose; Metformin; Mitochondrial function; Thymus
    DOI:  https://doi.org/10.1016/j.intimp.2022.108744
  12. Cell Death Dis. 2022 Apr 08. 13(4): 320
    Gut microbiota severely hampers the efficacy of NAD-lowering therapy in leukemia.
    Oussama ElMokh, Saki Matsumoto, Paulina Biniecka, Axel Bellotti, Karin Schaeuble, Francesco Piacente, Hector Gallart-Ayala, Julijana Ivanisevic, Ivan Stamenkovic, Alessio Nencioni, Aimable Nahimana, Michel A Duchosal.
      Most cancer cells have high need for nicotinamide adenine dinucleotide (NAD+) to sustain their survival. This led to the development of inhibitors of nicotinamide (NAM) phosphoribosyltransferase (NAMPT), the rate-limiting NAD+ biosynthesis enzyme from NAM. Such inhibitors kill cancer cells in preclinical studies but failed in clinical ones. To identify parameters that could negatively affect the therapeutic efficacy of NAMPT inhibitors and propose therapeutic strategies to circumvent such failure, we performed metabolomics analyses in tumor environment and explored the effect of the interaction between microbiota and cancer cells. Here we show that tumor environment enriched in vitamin B3 (NAM) or nicotinic acid (NA) significantly lowers the anti-tumor efficacy of APO866, a prototypic NAMPT inhibitor. Additionally, bacteria (from the gut, or in the medium) can convert NAM into NA and thus fuel an alternative NAD synthesis pathway through NA. This leads to the rescue from NAD depletion, prevents reactive oxygen species production, preserves mitochondrial integrity, blunts ATP depletion, and protects cancer cells from death.Our data in an in vivo preclinical model reveal that antibiotic therapy down-modulating gut microbiota can restore the anti-cancer efficacy of APO866. Alternatively, NAphosphoribosyltransferase inhibition may restore anti-cancer activity of NAMPT inhibitors in the presence of gut microbiota and of NAM in the diet.
    DOI:  https://doi.org/10.1038/s41419-022-04763-3
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