bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023‒09‒03
eleven papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Zinc Modulates Glutamine Metabolism in T Cells.
  2. Metabolic programs of T cell tissue residency empower tumour immunity.
  3. Cellular and molecular waypoints along the path of T cell exhaustion.
  4. Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.
  5. The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function.
  6. Accumulation of immune-suppressive CD4 + T cells in aging - tempering inflammaging at the expense of immunity.
  7. Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems.
  8. Boosting T cell immunity against cytomegalovirus: a potential strategy combating human aging and age-related diseases.
  9. Chemerin triggers migration of a CD8 T cell subset with natural killer cell functions.
  10. In-vivo screening implicates endoribonuclease Regnase-1 in modulating senescence-associated lysosomal changes.
  11. Lipid metabolic reprogramming of hepatic CD4+ T cells during SIV infection.
  1. Mol Nutr Food Res. 2023 Sep 01. e2300155
    Zinc Modulates Glutamine Metabolism in T Cells.
    Nergis Güzel, Lothar Rink, Henrike Josephine Fischer.
      SCOPE: Zinc and glutamine are well known to be essential for the function and polarization of immune cells. TH 17 cells are more frequently induced during zinc deficiency and cover their energy requirement mainly through glutaminolysis. A dysregulation of TH 17 cells can contribute to the development of autoimmune diseases. Both inhibition of glutaminolysis and zinc supplementation suppress experimental autoimmune encephalomyelitis in mice. Therefore, the aim of this study is to investigate whether zinc modulates glutaminolysis in T cells.METHODS AND RESULTS: CD3/CD28 stimulation and mixed lymphocytes culture are used as in vitro models for T cell activation. Then, the glutaminolysis is investigated on mRNA, protein, and functional level. Zinc deficiency and glutaminase (GLS) inhibition decrease immune responses in vitro. Furthermore, extracellular zinc and glutamine levels both modulate glutaminolysis by changing the expression of glutamine transporters and key enzymes. Intriguingly, zinc directly interferes with the activity of GLS both in a cell free system and in the cytosol.
    CONCLUSION: Besides T cell subset differentiation, zinc also impacts on the cellular metabolism by inhibiting glutaminolysis. This suggests that zinc deficiency can contribute to the development of autoimmune diseases whereas zinc supplementation can support their therapy.
    Keywords:  T cell; glutamine; glutaminolysis; immunology; zinc
    DOI:  https://doi.org/10.1002/mnfr.202300155
  2. Nature. 2023 Aug 30.
    Metabolic programs of T cell tissue residency empower tumour immunity.
    Miguel Reina-Campos, Maximilian Heeg, Kelly Kennewick, Ian T Mathews, Giovanni Galletti, Vida Luna, Quynhanh Nguyen, Hongling Huang, J Justin Milner, Kenneth H Hu, Amy Vichaidit, Natalie Santillano, Brigid S Boland, John T Chang, Mohit Jain, Sonia Sharma, Matthew F Krummel, Hongbo Chi, Steven J Bensinger, Ananda W Goldrath.
      Tissue resident memory CD8+ T (TRM) cells offer rapid and long-term protection at sites of reinfection1. Tumour-infiltrating lymphocytes with characteristics of TRM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting TRM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memory CD8+ T cell populations. We found that memory CD8+ T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate-cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where TRM cells interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memory T cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of TRM cell metabolism, we reveal how these programs can be leveraged to fuel memory CD8+ T cell formation in the context of acute infections and enhance antitumour immunity.
    DOI:  https://doi.org/10.1038/s41586-023-06483-w
  3. Sci Immunol. 2023 Sep;8(87): eadg3868
    Cellular and molecular waypoints along the path of T cell exhaustion.
    Xin Lan, Caitlin C Zebley, Ben Youngblood.
      Thirty years of foundational research investigating molecular and cellular mechanisms promoting T cell exhaustion are now enabling rational design of T cell-based therapies for the treatment of chronic infections and cancer. Once described as a static cell fate, it is now well appreciated that the developmental path toward exhaustion is composed of a heterogeneous pool of cells with varying degrees of effector potential that ultimately converge on a terminally differentiated state. Recent description of the developmental stages along the differentiation trajectory of T cell exhaustion has provided insight into past immunotherapeutic success and future opportunities. Here, we discuss the hallmarks of distinct developmental stages occurring along the path to T cell dysfunction and the impact of these discrete CD8+ T cell fates on cancer immunotherapy.
    DOI:  https://doi.org/10.1126/sciimmunol.adg3868
  4. bioRxiv. 2023 Aug 19. pii: 2023.08.17.553736. [Epub ahead of print]
    Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.
    Paul V Dellorusso, Melissa A Proven, Fernando J Calero-Nieto, Xiaonan Wang, Carl A Mitchell, Felix Hartmann, Meelad Amouzgar, Patricia Favaro, Andrew DeVilbiss, James W Swann, Theodore T Ho, Zhiyu Zhao, Sean C Bendall, Sean Morrison, Berthold Göttgens, Emmanuelle Passegué.
      Aging of the hematopoietic system promotes various blood, immune and systemic disorders and is largely driven by hematopoietic stem cell (HSC) dysfunction ( 1 ). Autophagy is central for the benefits associated with activation of longevity signaling programs ( 2 ), and for HSC function and response to nutrient stress ( 3,4 ). With age, a subset of HSCs increases autophagy flux and preserves some regenerative capacity, while the rest fail to engage autophagy and become metabolically overactivated and dysfunctional ( 4 ). However, the signals that promote autophagy in old HSCs and the mechanisms responsible for the increased regenerative potential of autophagy-activated old HSCs remain unknown. Here, we demonstrate that autophagy activation is an adaptive survival response to chronic inflammation in the aging bone marrow (BM) niche ( 5 ). We find that inflammation impairs glucose metabolism and suppresses glycolysis in aged HSCs through Socs3-mediated impairment of AKT/FoxO-dependent signaling. In this context, we show that inflammation-mediated autophagy engagement preserves functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we demonstrate that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glucose uptake and glycolytic flux and significantly improves old HSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset old HSC glycolytic and regenerative capacity.One-Sentence Summary: Autophagy compensates for chronic inflammation-induced metabolic deregulation in old HSCs, and its transient modulation can reset old HSC glycolytic and regenerative capacity.
    DOI:  https://doi.org/10.1101/2023.08.17.553736
  5. Cell Rep. 2023 Aug 24. pii: S2211-1247(23)01024-0. [Epub ahead of print]42(9): 113013
    The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function.
    Iosifina P Foskolou, Pedro P Cunha, Elena Sánchez-López, Eleanor A Minogue, Benoît P Nicolet, Aurélie Guislain, Christian Jorgensen, Sarantos Kostidis, Nordin D Zandhuis, Laura Barbieri, David Bargiela, Demitris Nathanael, Petros A Tyrakis, Asis Palazon, Martin Giera, Monika C Wolkers, Randall S Johnson.
      2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in cluster of differentiation (CD)8+ T cell biology, where we find they have highly divergent effects on proliferation, differentiation, and T cell function. We show here an analysis of structural determinants that likely underlie these differential effects on specific α-ketoglutarate (αKG)-dependent enzymes. Treatment of CD8+ T cells with exogenous S-2HG, but not R-2HG, increased CD8+ T cell fitness in vivo and enhanced anti-tumor activity. These data show that S-2HG and R-2HG should be considered as two distinct and important actors in the regulation of T cell function.
    Keywords:  2-hydroxyglutarate; CD8+ T cell function; CD8+ T cell memory; CP: Immunology; adoptive cell transfer; oncometabolites
    DOI:  https://doi.org/10.1016/j.celrep.2023.113013
  6. Semin Immunol. 2023 Aug 24. pii: S1044-5323(23)00127-6. [Epub ahead of print]70 101836
    Accumulation of immune-suppressive CD4 + T cells in aging - tempering inflammaging at the expense of immunity.
    Alyssa L Thomas, Alzbeta Godarova, Joseph A Wayman, Emily R Miraldi, David A Hildeman, Claire A Chougnet.
      The 'immune risk profile' has been shown to predict mortality in the elderly, highlighting the need to better understand age-related immune dysfunction. While aging leads to many defects affecting all arms of the immune system, this review is focused on the accrual of immuno-suppressive CD4 + T cell populations, including FoxP3 + regulatory T cells, and subsets of IL-10-producing T follicular helper cells. New data suggest that such accumulations constitute feedback mechanisms to temper the ongoing progressive low-grade inflammation that develops with age, the so-called "inflammaging", and by doing so, how they have the potential to promote healthier aging. However, they also impair effector immune responses, notably to infections, or vaccines. These studies also reinforce the idea that the aged immune system should not be considered as a poorly functional version of the young one, but more as a dynamic system in which CD4 + T cells, and other immune/non-immune subsets, differentiate, interact with their milieu and function differently than in young hosts. A better understanding of these unique interactions is thus needed to improve effector immune responses in the elderly, while keeping inflammaging under control.
    Keywords:  Aging; IL-10; Inflammaging; Regulatory T cells; T follicular helper cells
    DOI:  https://doi.org/10.1016/j.smim.2023.101836
  7. Nat Aging. 2023 Aug 31.
    Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems.
    Mukul Girotra, Yi-Hsuan Chiang, Melanie Charmoy, Pierpaolo Ginefra, Helen Carrasco Hope, Charles Bataclan, Yi-Ru Yu, Frederica Schyrr, Fabien Franco, Hartmut Geiger, Stephane Cherix, Ping-Chih Ho, Olaia Naveiras, Johan Auwerx, Werner Held, Nicola Vannini.
      Aging compromises hematopoietic and immune system functions, making older adults especially susceptible to hematopoietic failure, infections and tumor development, and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward the myeloid lineage (myeloid bias)1,2. These processes are accompanied by an aberrant accumulation of mitochondria in HSCs3. The administration of the mitochondrial modulator urolithin A corrects mitochondrial function in HSCs and completely restores the blood reconstitution capability of 'old' HSCs. Moreover, urolithin A-supplemented food restores lymphoid compartments, boosts HSC function and improves the immune response against viral infection in old mice. Altogether our results demonstrate that boosting mitochondrial recycling reverts the aging phenotype in the hematopoietic and immune systems.
    DOI:  https://doi.org/10.1038/s43587-023-00473-3
  8. Signal Transduct Target Ther. 2023 Sep 01. 8(1): 325
    Boosting T cell immunity against cytomegalovirus: a potential strategy combating human aging and age-related diseases.
    Matthias Wirth, Walburgis Brenner, Oliver H Krämer.
      
    DOI:  https://doi.org/10.1038/s41392-023-01590-6
  9. Mol Ther. 2023 Aug 28. pii: S1525-0016(23)00447-1. [Epub ahead of print]
    Chemerin triggers migration of a CD8 T cell subset with natural killer cell functions.
    Romain Ballet, Melissa LaJevic, Noelle Huskey-Mullin, Rachel Roach, Kevin Brulois, Ying Huang, Muhammad A Saeed, Ha X Dang, Russell K Pachynski, Elizabeth Wilson, Eugene C Butcher, Brian A Zabel.
      The recruitment of cells with effector functions into the tumor microenvironment holds potential for delaying cancer progression. We show that subsets of human CD28- effector CD8 T cells, of CCR7- CD45RO+ effector memory and CCR7- CD45RO- effector memory RA phenotypes, express the chemerin receptor CMKLR1 and bind chemerin via the receptor. CMKLR1-expressing human CD8 effector memory T cells present gene, protein and cytotoxic features of NK cells. Active chemerin promotes chemotaxis of CMKLR1-expressing CD8 effector memory cells and triggers activation of the α4β1 integrin. In an experimental prostate tumor mouse model, chemerin expression is downregulated in the tumor microenvironment, which is associated with few tumor-infiltrating CD8+ T cells, while forced overexpression of chemerin by mouse prostate cancer cells leads to an accumulation of intra-tumor CD8+ T cells. Furthermore, α4 integrin blockade abrogated the chemerin-dependent recruitment of CD8+ T effector memory cells into implanted prostate tumors in vivo. The results identify a role for chemerin:CMKLR1 in defining a specialized NK-like CD8 T cell, and suggest the use of chemerin-dependent modalities to target effector CMKLR1-expressing T cells to tumor microenvironment for immunotherapeutic purposes.
    DOI:  https://doi.org/10.1016/j.ymthe.2023.08.015
  10. Geroscience. 2023 Aug 29.
    In-vivo screening implicates endoribonuclease Regnase-1 in modulating senescence-associated lysosomal changes.
    Richard Venz, Anita Goyala, Abel Soto-Gamez, Tugce Yenice, Marco Demaria, Collin Y Ewald.
      Accumulation of senescent cells accelerates aging and age-related diseases, whereas preventing this accumulation extends the lifespan in mice. A characteristic of senescent cells is increased staining with β-galactosidase (β-gal) ex vivo. Here, we describe a progressive accumulation of β-gal staining in the model organism C. elegans during aging. We show that distinct pharmacological and genetic interventions targeting the mitochondria and the mTORC1 to the nuclear core complex axis, the non-canonical apoptotic, and lysosomal-autophagy pathways slow the age-dependent accumulation of β-gal. We identify a novel gene, rege-1/Regnase-1/ZC3H12A/MCPIP1, modulating β-gal staining via the transcription factor ets-4/SPDEF. We demonstrate that knocking down Regnase-1 in human cell culture prevents senescence-associated β-gal accumulation. Our data provide a screening pipeline to identify genes and drugs modulating senescence-associated lysosomal phenotypes.
    Keywords:  Beta-gal; Longevity; Metformin; Senescence; Senolytic
    DOI:  https://doi.org/10.1007/s11357-023-00909-z
  11. Microbiol Spectr. 2023 Sep 01. e0168723
    Lipid metabolic reprogramming of hepatic CD4+ T cells during SIV infection.
    Julien A Clain, Steven Boutrais, Juliette Dewatines, Gina Racine, Henintsoa Rabezanahary, Arnaud Droit, Ouafa Zghidi-Abouzid, Jérôme Estaquier.
      While liver inflammation is associated with AIDS, little is known so far about hepatic CD4+ T cells. By using the simian immunodeficiency virus (SIV)-infected rhesus macaque (RM) model, we aimed to characterize CD4+ T cells. The phenotype of CD4+ T cells was assessed by flow cytometry from uninfected (n = 3) and infected RMs, with either SIVmac251 (n = 6) or SHIVSF162p3 (n = 6). After cell sorting of hepatic CD4+ T cells, viral DNA quantification and RNA sequencing were performed.Thus, we demonstrated that liver CD4+ T cells strongly expressed the SIV coreceptor, CCR5. We showed that viremia was negatively correlated with the percentage of hepatic effector memory CD4+ T cells. Consistent with viral sensing, inflammatory and interferon gene transcripts were increased. We also highlighted the presence of harmful CD4+ T cells expressing GZMA and members of TGFB that could contribute to fuel inflammation and fibrosis. Whereas RNA sequencing demonstrated activated CD4+ T cells displaying higher levels of mitoribosome and membrane lipid synthesis transcripts, few genes were related to glycolysis and oxidative phosphorylation, which are essential to sustain activated T cells. Furthermore, we observed lower levels of mitochondrial DNA and higher levels of genes associated with damaged organelles (reticulophagy and mitophagy). Altogether, our data revealed that activated hepatic CD4+ T cells are reprogrammed to lipid metabolism. Thus, strategies aiming to reprogram T cell metabolism with effector function could be of interest for controlling viral infection and preventing liver disorders.IMPORTANCEHuman immunodeficiency virus (HIV) infection may cause liver diseases, associated with inflammation and tissue injury, contributing to comorbidity in people living with HIV. Paradoxically, the contribution of hepatic CD4+ T cells remains largely underestimated. Herein, we used the model of simian immunodeficiency virus (SIV)-infected rhesus macaques to access liver tissue. Our work demonstrates that hepatic CD4+ T cells express CCR5, the main viral coreceptor, and are infected. Viral infection is associated with the presence of inflamed and activated hepatic CD4+ T cells expressing cytotoxic molecules. Furthermore, hepatic CD4+ T cells are reprogrammed toward lipid metabolism after SIV infection. Altogether, our findings shed new light on hepatic CD4+ T cell profile that could contribute to liver injury following viral infection.
    Keywords:  AIDS; CCR5; CD4; PD-1; SIV; autophagy; cytotoxic; ferroptosis; granzyme; lipid; liver; metabolism; viral reservoir
    DOI:  https://doi.org/10.1128/spectrum.01687-23
This page is being maintained by Thomas Krichel. It was last updated on 2023‒09‒03 at 7:22.