bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–02–19
eightteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Metabolism and epigenetics at the heart of T cell function.
  2. Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory T cell differentiation in vitro.
  3. Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model.
  4. Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development.
  5. Transient EZH2 suppression by Tazemetostat during in vitro expansion maintains T cell stemness and improves adoptive T cell therapy.
  6. Methionine adenosyltransferase2A inhibition restores metabolism to improve regenerative capacity and strength of aged skeletal muscle.
  7. Age is just a number: long-lasting T-cell immunity can span several lifetimes.
  8. Hematopoietic Stem Cell Aging and Leukemia Transformation.
  9. Selective depletion of naïve T cells by targeting CD45RA.
  10. OX40 agonism enhances PD-L1 checkpoint blockade by shifting the cytotoxic T cell differentiation spectrum.
  11. CD8 T cell diversification: asymmetric cell division and its functional implications.
  12. Inactivation mechanism of an immunoglobulin modulator of the T-cell potassium channel Kv1.3.
  13. Recombinant FOXN1 fusion protein increases T cell generation in aged mice.
  14. Decreased thymic output predicts progression of chronic kidney disease.
  15. XCR1+ DCs are critical for T cell-mediated immunotherapy of chronic viral infections.
  16. Coupling of autophagy and the mitochondrial intrinsic apoptosis pathway modulates proteostasis and ageing in Caenorhabditis elegans.
  17. The outer mitochondrial membrane protein TMEM11 demarcates spatially restricted BNIP3/BNIP3L-mediated mitophagy.
  18. Principles of regulatory T cell function.
  1. Trends Immunol. 2023 Feb 09. pii: S1471-4906(23)00002-9. [Epub ahead of print]
    Metabolism and epigenetics at the heart of T cell function.
    Leticia Soriano-Baguet, Dirk Brenner.
      T cell subsets adapt and rewire their metabolism according to their functions and surrounding microenvironment. Whereas naive T cells rely on mitochondrial metabolic pathways characterized by low nutrient requirements, effector T cells induce kinetically faster pathways to generate the biomass and energy needed for proliferation and cytokine production. Recent findings support the concept that alterations in metabolism also affect the epigenetics of T cells. In this review we discuss the connections between T cell metabolism and epigenetic changes such as histone post-translational modifications (PTMs) and DNA methylation, as well as the 'extra-metabolic' roles of metabolic enzymes and molecules. These findings collectively point to a new group of potential therapeutic targets for the treatment of T cell-dependent autoimmune diseases and cancers.
    Keywords:  DNA; NAD; T cells; acetylation; epigentics; histone; metabolism; methylation
    DOI:  https://doi.org/10.1016/j.it.2023.01.002
  2. Res Sq. 2023 Jan 27. pii: rs.3.rs-2464392. [Epub ahead of print]
    Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory T cell differentiation in vitro.
    Tatiana N Tarasenko, Payal Banerjee, Julio Gomez-Rodriguez, Derek Gildea, Suiyuan Zhang, Tyra Wolfsberg, Lisa M Jenkins, Nisc Comparative Sequencing Program, Peter J McGuire.
      Background Modulation of metabolic flux through pyruvate dehydrogenase complex (PDC) plays an important role in T cell activation and differentiation. PDC sits at the transition between glycolysis and the tricarboxylic acid cycle and is a major producer of acetyl-CoA, marking it as a potential metabolic and epigenetic node. Methods To understand the role of pyruvate dehydrogenase complex in T cell differentiation, we generated mice deficient in T cell pyruvate dehydrogenase E1A ( Pdha ) subunit using a CD4-cre recombinase-based strategy. To control for the contribution of exogenous metabolites in vivo, we conducted our T cell functional studies in vitro. T cells were differentiated into memory and effector T cells using standardized protocols. Cells were analyzed using stable isotopic tracing studies, metabolomics, RNAseq, ATACseq, ChIPseq and histone proteomics. Results Herein, we show that genetic ablation of PDC activity in T cells ( TPdh -/- ) leads to marked perturbations in glycolysis, the tricarboxylic acid cycle, and OXPHOS. Due to depressed OXPHOS, TPdh -/- T cells became dependent upon substrate level phosphorylation via glycolysis. Due to the block of PDC activity, histone acetylation was reduced, as were most other types of post translational modifications. Transcriptional and functional profiling revealed abnormal CD8 + memory T cell differentiation in vitro. Conclusions Collectively, our data indicate that PDC integrates the metabolome and epigenome in memory T cell differentiation. Targeting this metabolic and epigenetic node can have widespread ramifications on cellular function.
    DOI:  https://doi.org/10.21203/rs.3.rs-2464392/v1
  3. Front Oncol. 2023 ;13 1107484
    Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model.
    Nathalie Babl, Joshua Hofbauer, Carina Matos, Florian Voll, Ayse Nur Menevse, Michael Rechenmacher, Ruth Mair, Philipp Beckhove, Wolfgang Herr, Peter J Siska, Kathrin Renner, Marina Kreutz, Annette Schnell.
       Introduction: The discovery of immune checkpoints and the development of their specific inhibitors was acclaimed as a major breakthrough in cancer therapy. However, only a limited patient cohort shows sufficient response to therapy. Hence, there is a need for identifying new checkpoints and predictive biomarkers with the objective of overcoming immune escape and resistance to treatment. Having been associated with both, treatment response and failure, LDL seems to be a double-edged sword in anti-PD1 immunotherapy. Being embedded into complex metabolic conditions, the impact of LDL on distinct immune cells has not been sufficiently addressed. Revealing the effects of LDL on T cell performance in tumor immunity may enable individual treatment adjustments in order to enhance the response to routinely administered immunotherapies in different patient populations. The object of this work was to investigate the effect of LDL on T cell activation and tumor immunity in-vitro.
    Methods: Experiments were performed with different LDL dosages (LDLlow = 50 μg/ml and LDLhigh = 200 μg/ml) referring to medium control. T cell phenotype, cytokines and metabolism were analyzed. The functional relevance of our findings was studied in a HCT116 spheroid model in the context of anti-PD-1 blockade.
    Results: The key points of our findings showed that LDLhigh skewed the CD4+ T cell subset into a central memory-like phenotype, enhanced the expression of the co-stimulatory marker CD154 (CD40L) and significantly reduced secretion of IL-10. The exhaustion markers PD-1 and LAG-3 were downregulated on both T cell subsets and phenotypical changes were associated with a balanced T cell metabolism, in particular with a significant decrease of reactive oxygen species (ROS). T cell transfer into a HCT116 spheroid model resulted in a significant reduction of the spheroid viability in presence of an anti-PD-1 antibody combined with LDLhigh.
    Discussion: Further research needs to be conducted to fully understand the impact of LDL on T cells in tumor immunity and moreover, to also unravel LDL effects on other lymphocytes and myeloid cells for improving anti-PD-1 immunotherapy. The reason for improved response might be a resilient, less exhausted phenotype with balanced ROS levels.
    Keywords:  CD154 (CD40L); LDL (low-density lipoprotein); PD-1; central memory (T) CM; cholesterol; immunotherapy; reactive oxygen species; spheroid model
    DOI:  https://doi.org/10.3389/fonc.2023.1107484
  4. Nat Immunol. 2023 Feb 16.
    Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development.
    Stefanie Scherer, Susanne G Oberle, Kristiyan Kanev, Ann-Katrin Gerullis, Ming Wu, Gustavo P de Almeida, Daniel J Puleston, Francesc Baixauli, Lilian Aly, Alessandro Greco, Tamar Nizharadze, Nils B Becker, Madlaina V Hoesslin, Lara V Donhauser, Jacqueline Berner, Talyn Chu, Hayley A McNamara, Zeynep Esencan, Patrick Roelli, Christine Wurmser, Ingo Kleiter, Maria J G T Vehreschild, Christoph A Mayer, Percy Knolle, Martin Klingenspor, Valeria Fumagalli, Matteo Iannacone, Martin Prlic, Thomas Korn, Erika L Pearce, Thomas Höfer, Anna M Schulz, Dietmar Zehn.
      Blocking pyrimidine de novo synthesis by inhibiting dihydroorotate dehydrogenase is used to treat autoimmunity and prevent expansion of rapidly dividing cell populations including activated T cells. Here we show memory T cell precursors are resistant to pyrimidine starvation. Although the treatment effectively blocked effector T cells, the number, function and transcriptional profile of memory T cells and their precursors were unaffected. This effect occurred in a narrow time window in the early T cell expansion phase when developing effector, but not memory precursor, T cells are vulnerable to pyrimidine starvation. This vulnerability stems from a higher proliferative rate of early effector T cells as well as lower pyrimidine synthesis capacity when compared with memory precursors. This differential sensitivity is a drug-targetable checkpoint that efficiently diminishes effector T cells without affecting the memory compartment. This cell fate checkpoint might therefore lead to new methods to safely manipulate effector T cell responses.
    DOI:  https://doi.org/10.1038/s41590-023-01436-x
  5. bioRxiv. 2023 Feb 07. pii: 2023.02.07.527459. [Epub ahead of print]
    Transient EZH2 suppression by Tazemetostat during in vitro expansion maintains T cell stemness and improves adoptive T cell therapy.
    Yingqin Hou, Jaroslav Zak, Yujie Shi, Isaraphorn Pratumchai, Brandon Dinner, Wenjian Wang, Ke Qin, Evan Weber, John R Teijaro, Peng Wu.
      The histone methyltransferase enhancer of zeste homolog 2 (EZH2)-mediated epigenetic regulation of T cell differentiation in acute infection has been extensively investigated. However, the role of EZH2 in T cell exhaustion remains under-explored. Here, using in vitro exhaustion models, we demonstrated that transient inhibition of EZH2 in T cells before the phenotypic onset of exhaustion with a clinically approved inhibitor, Tazemetastat, delayed their dysfunctional progression and maintained T cell stemness and polyfunctionality while having no negative impact on cell proliferation. Tazemetestat induced T cell epigenetic reprogramming and increased the expression of the self-renewing T cell transcription factor TCF1 by reducing its promoter H3K27 methylation preferentially in rapidly dividing T cells. In a murine melanoma model, T cells pre-treated with tazemetastat exhibited a superior response to anti-PD-1 blockade therapy after adoptive transfer. Collectively, these data unveil the potential of transient epigenetic reprogramming as a potential intervention to be combined with checkpoint blockade for immune therapy.
    DOI:  https://doi.org/10.1101/2023.02.07.527459
  6. Nat Commun. 2023 Feb 16. 14(1): 886
    Methionine adenosyltransferase2A inhibition restores metabolism to improve regenerative capacity and strength of aged skeletal muscle.
    Nika Rajabian, Izuagie Ikhapoh, Shahryar Shahini, Debanik Choudhury, Ramkumar Thiyagarajan, Aref Shahini, Joseph Kulczyk, Kendall Breed, Shilpashree Saha, Mohamed Alaa Mohamed, Susan B Udin, Aimee Stablewski, Kenneth Seldeen, Bruce R Troen, Kirkwood Personius, Stelios T Andreadis.
      We investigate the age-related metabolic changes that occur in aged and rejuvenated myoblasts using in vitro and in vivo models of aging. Metabolic and signaling experiments reveal that human senescent myoblasts and myoblasts from a mouse model of premature aging suffer from impaired glycolysis, insulin resistance, and generate Adenosine triphosphate by catabolizing methionine via a methionine adenosyl-transferase 2A-dependant mechanism, producing significant levels of ammonium that may further contribute to cellular senescence. Expression of the pluripotency factor NANOG downregulates methionine adenosyltransferase 2 A, decreases ammonium, restores insulin sensitivity, increases glucose uptake, and enhances muscle regeneration post-injury. Similarly, selective inhibition of methionine adenosyltransferase 2 A activates Akt2 signaling, repairs pyruvate kinase, restores glycolysis, and enhances regeneration, which leads to significant enhancement of muscle strength in a mouse model of premature aging. Collectively, our investigation indicates that inhibiting methionine metabolism may restore age-associated impairments with significant gain in muscle function.
    DOI:  https://doi.org/10.1038/s41467-023-36483-3
  7. Immunol Cell Biol. 2023 Feb 16.
    Age is just a number: long-lasting T-cell immunity can span several lifetimes.
    Julian J Freen-van Heeren, Rianne Opstelten.
      
    Keywords:  T-cell immunity; lifetime immunity; memory T cells
    DOI:  https://doi.org/10.1111/imcb.12632
  8. Blood. 2023 Feb 17. pii: blood.2022017933. [Epub ahead of print]
    Hematopoietic Stem Cell Aging and Leukemia Transformation.
    Patricia A Colom Díaz, Jayna J Mistry, Jennifer J Trowbridge.
      With aging, hematopoietic stem cells (HSCs) have an impaired ability to regenerate, differentiate, and produce the entire repertoire of mature blood and immune cells. Due to dysfunctional hematopoiesis, the incidence of hematologic malignancies increases in elderly individuals. Here, we provide an update on HSC-intrinsic and HSC-extrinsic factors and processes recently discovered to contribute to functional decline of HSCs during aging. In addition, we discuss targets and timing of intervention approaches to maintain HSC function during aging and the extent to which these same targets may prevent or delay transformation to hematologic malignancies.
    DOI:  https://doi.org/10.1182/blood.2022017933
  9. Front Oncol. 2022 ;12 1009143
    Selective depletion of naïve T cells by targeting CD45RA.
    Swati Naik, Brandon M Triplett.
      
    Keywords:  CD45RA depletion; Hematopoietic Cell Transplantation; T-cell depletion; memory T cells; naive T cell depletion
    DOI:  https://doi.org/10.3389/fonc.2022.1009143
  10. Cell Rep Med. 2023 Feb 07. pii: S2666-3791(23)00031-9. [Epub ahead of print] 100939
    OX40 agonism enhances PD-L1 checkpoint blockade by shifting the cytotoxic T cell differentiation spectrum.
    Tetje C van der Sluis, Guillaume Beyrend, Esmé T I van der Gracht, Tamim Abdelaal, Simon P Jochems, Robert A Belderbos, Thomas H Wesselink, Suzanne van Duikeren, Floortje J van Haften, Anke Redeker, Laura F Ouboter, Elham Beyranvand Nejad, Marcel Camps, Kees L M C Franken, Margot M Linssen, Peter Hohenstein, Noel F C C de Miranda, Hailiang Mei, Adriaan D Bins, John B A G Haanen, Joachim G Aerts, Ferry Ossendorp, Ramon Arens.
      Immune checkpoint therapy (ICT) has the power to eradicate cancer, but the mechanisms that determine effective therapy-induced immune responses are not fully understood. Here, using high-dimensional single-cell profiling, we interrogate whether the landscape of T cell states in the peripheral blood predict responses to combinatorial targeting of the OX40 costimulatory and PD-1 inhibitory pathways. Single-cell RNA sequencing and mass cytometry expose systemic and dynamic activation states of therapy-responsive CD4+ and CD8+ T cells in tumor-bearing mice with expression of distinct natural killer (NK) cell receptors, granzymes, and chemokines/chemokine receptors. Moreover, similar NK cell receptor-expressing CD8+ T cells are also detected in the blood of immunotherapy-responsive cancer patients. Targeting the NK cell and chemokine receptors in tumor-bearing mice shows the functional importance of these receptors for therapy-induced anti-tumor immunity. These findings provide a better understanding of ICT and highlight the use and targeting of dynamic biomarkers on T cells to improve cancer immunotherapy.
    Keywords:  T cells; immune checkpoint therapy; immunotherapy; mass cytometry; predictive biomarkers; single-cell RNA sequencing; systemic immune activation
    DOI:  https://doi.org/10.1016/j.xcrm.2023.100939
  11. Eur J Immunol. 2023 Feb 14. e2250225
    CD8 T cell diversification: asymmetric cell division and its functional implications.
    Fabienne Gräbnitz, Annette Oxenius.
      Establishment of cellular diversity is a basic requirement for the development of multicellular organisms. Cellular diversification can be induced by asymmetric cell division (ACD), during which the emerging two daughter cells unequally inherit lineage specific cargo (including transcription factors, receptors for specific signaling inputs, metabolic platforms and possibly different epigenetic landscapes), resulting in two daughter cells endowed with different fates. While ACD is strongly involved in lineage choices in mammalian stem cells, its role in fate diversification in lineage committed cell subsets that still exhibit plastic potential, such as T cells, is currently investigated. In this review, we focus predominantly on the role of ACD in fate diversification of CD8 T cells. Further, we discuss the impact of differential T cell receptor stimulation strengths and differentiation history on ACD-mediated fate diversification and highlight a particular importance of ACD in the development of memory CD8 T cells upon high affinity stimulation conditions. This article is protected by copyright. All rights reserved.
    Keywords:  Asymmetric cell division; CD8 T cells; Cell fate; Memory T cells; T cell differentiation
    DOI:  https://doi.org/10.1002/eji.202250225
  12. Biophys J. 2023 Feb 10. pii: S0006-3495(22)01217-6. [Epub ahead of print]122(3S1): 13a-14a
    Inactivation mechanism of an immunoglobulin modulator of the T-cell potassium channel Kv1.3.
    Purushotham Selvakumar, Ana I Fernández-Mariño, Bing Wang, William J Rice, Joel R Meyerson, Kenton J Swartz.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.301
  13. Res Sq. 2023 Feb 08. pii: rs.3.rs-2557067. [Epub ahead of print]
    Recombinant FOXN1 fusion protein increases T cell generation in aged mice.
    Jin Zhao, Zhenzhen Zhang, Kuan Chen Lai, Laijun Lai.
      Background: Although the thymus continues to export T cells throughout life, it undergoes a profound involution/atrophy with age, resulting in decreased numbers of T cells in the older adult, which has direct etiological linkages with many diseases. T cell development in the thymus is dependent on the thymic microenvironment, in which thymic epithelial cells (TECs) are the major component. However, TECs undergo both a qualitative and quantitative loss during aging, which is believed to be the major factor responsible for age-dependent thymic atrophy. FOXN1 plays a critical role in TEC development and adult TECs maintenance. We have previously reported that intrathymic injection of a recombinant (r) protein containing FOXN1 and a protein transduction domain increases the number of TECs in mice, leading to enhanced thymopoiesis. However, intrathymic injection may not be an ideal choice for clinical applications. In this study, we produce a rFOXN1 fusion protein containing the N-terminal of CCR9, FOXN1 and a protein transduction domain. Results: We show here that, when injected intravenously into aged mice, the rFOXN1 fusion protein migrates into the thymus and enhances thymopoiesis, resulting in increased T cell generation in the thymus and increased number of T cells in peripheral lymphoid organ. Conclusions: Our results suggest that the rFOXN1 fusion protein has the potential to be used in preventing and treating T cell immunodeficiency in the older adult.
    DOI:  https://doi.org/10.21203/rs.3.rs-2557067/v1
  14. Immun Ageing. 2023 Feb 14. 20(1): 8
    Decreased thymic output predicts progression of chronic kidney disease.
    Kenichiro Iio, Daijiro Kabata, Rei Iio, Shinichi Shibamoto, Yuuki Watanabe, Masashi Morita, Yosuke Imai, Masaki Hatanaka, Hiroki Omori, Yoshitaka Isaka.
       BACKGROUND: Chronic kidney disease (CKD) is age-related disease, and decreased renal function is associated with the premature aging of T cells and increased incidence of other age-related diseases. However, the relationship between T cell senescence and CKD progression remains unclear. Here, we investigated the relationship between T cell senescence, as indicated by decreased thymic output and increased proportion of highly differentiated CD28- T cells, and CKD progression.
    RESULTS: A total of 175 patients with non-dialysis-dependent CKD were enrolled in this study. Thymic output was assessed based on the CD45RA+CD31+CD4+ cell (recent thymic emigrant [RTE]) counts (RTEs) (/mm3) and the proportion of RTE among CD4+ T cells (RTE%). Highly differentiated T cells were assessed based on the proportion of CD28- cells among CD4+ T cells (CD28-/CD4+) and CD28- cells among CD8+ T cells (CD28-/CD8+). The primary outcome was estimated glomerular filtration rate (eGFR) decline of ≥40% or initiation of renal replacement therapy. The association between T cell senescence and renal outcomes was examined using Cox proportional hazards models and restricted cubic splines. The median age was 73 years, 33% were women, and the median eGFR was 26 mL/min/1.73 m2. The median RTEs, RTE%, CD28-/CD4+, and CD28-/CD8+ were 97.5/mm3, 16.2, 5.3, and 49.7%, respectively. After a median follow-up of 1.78 years, renal outcomes were observed in 71 patients. After adjusting for age, sex, eGFR, proteinuria, diabetes, and cytomegalovirus seropositivity, decreased RTEs, which corresponded to decreased thymic output, significantly and monotonically increased the risk of poor renal outcome (p = 0.04), and decreased RTE% and increased highly differentiated CD28-/CD4+ T cells also tended to monotonically increase the risk (p = 0.074 and p = 0.056, respectively), but not CD28-/CD8+ T cells.
    CONCLUSIONS: Decreased thymic output in CKD patients, as well as increased highly differentiated CD4+ T cells, predicted renal outcomes. Thus, the identification of patients prone to CKD progression using T cell senescence, particularly decreased RTE as a biomarker, may help to prevent progression to end-stage kidney disease.
    Keywords:  Chronic kidney disease; Recent thymic emigrants; Renal outcomes; T cell senescence
    DOI:  https://doi.org/10.1186/s12979-023-00333-z
  15. Cell Rep. 2023 Feb 14. pii: S2211-1247(23)00134-1. [Epub ahead of print]42(2): 112123
    XCR1+ DCs are critical for T cell-mediated immunotherapy of chronic viral infections.
    Eva Domenjo-Vila, Valentina Casella, Ryutaro Iwabuchi, Even Fossum, Mireia Pedragosa, Quim Castellví, Paula Cebollada Rica, Tsuneyasu Kaisho, Kazutaka Terahara, Gennady Bocharov, Jordi Argilaguet, Andreas Meyerhans.
      The contribution of cross-presenting XCR1+ dendritic cells (DCs) and SIRPα+ DCs in maintaining T cell function during exhaustion and immunotherapeutic interventions of chronic infections remains poorly characterized. Using the mouse model of chronic LCMV infection, we found that XCR1+ DCs are more resistant to infection and highly activated compared with SIRPα+ DCs. Exploiting XCR1+ DCs via Flt3L-mediated expansion or XCR1-targeted vaccination notably reinvigorates CD8+ T cells and improves virus control. Upon PD-L1 blockade, XCR1+ DCs are not required for the proliferative burst of progenitor exhausted CD8+ T (TPEX) cells but are indispensable to sustain the functionality of exhausted CD8+ T (TEX) cells. Combining anti-PD-L1 therapy with increased frequency of XCR1+ DCs improves functionality of TPEX and TEX subsets, while increase of SIRPα+ DCs dampened their proliferation. Together, this demonstrates that XCR1+ DCs are crucial for the success of checkpoint inhibitor-based therapies through differential activation of exhausted CD8+ T cell subsets.
    Keywords:  CP: Immunology; Flt3L; LCMV; SIRPɑ+ DCs; T cell exhaustion; XCR1+ DCs; anti-PD-L1; chronic infection; immunotherapy; therapeutic vaccination
    DOI:  https://doi.org/10.1016/j.celrep.2023.112123
  16. Cell Death Dis. 2023 Feb 11. 14(2): 110
    Coupling of autophagy and the mitochondrial intrinsic apoptosis pathway modulates proteostasis and ageing in Caenorhabditis elegans.
    Christina Ploumi, Emmanouil Kyriakakis, Nektarios Tavernarakis.
      Mitochondria preserve metabolic homeostasis and integrate stress signals, to trigger cytoprotective, or cell death pathways. Mitochondrial homeostasis and function decline with age. The mechanisms underlying the deterioration of mitochondrial homeostasis during ageing, or in age-associated pathologies, remain unclear. Here, we show that CISD-1, a mitochondrial iron-sulfur cluster binding protein, implicated in the pathogenesis of Wolfram neurodegenerative syndrome type 2, modulates longevity in the nematode Caenorhabditis elegans by engaging autophagy and the mitochondrial intrinsic apoptosis pathway. The anti-apoptotic protein CED-9 is the downstream effector that mediates CISD-1-dependent effects on proteostasis, neuronal integrity and lifespan. Moreover, intracellular iron abundance is critical for CISD-1 function, since mild iron supplementation is sufficient to decelerate ageing and partly ameliorate the disturbed mitochondrial bioenergetics and proteostasis of CISD-1 deficient animals. Our findings reveal that CISD-1 serves as a mechanistic link between autophagy and the apoptotic pathway in mitochondria to differentially modulate organismal proteostasis and ageing, and suggest novel approaches which could facilitate the treatment of Wolfram Syndrome or related diseases.
    DOI:  https://doi.org/10.1038/s41419-023-05638-x
  17. J Cell Biol. 2023 Apr 03. pii: e202204021. [Epub ahead of print]222(4):
    The outer mitochondrial membrane protein TMEM11 demarcates spatially restricted BNIP3/BNIP3L-mediated mitophagy.
    Mehmet Oguz Gok, Olivia M Connor, Xun Wang, Cameron J Menezes, Claire B Llamas, Prashant Mishra, Jonathan R Friedman.
      Mitochondria play critical roles in cellular metabolism and to maintain their integrity, they are regulated by several quality control pathways, including mitophagy. During BNIP3/BNIP3L-dependent receptor-mediated mitophagy, mitochondria are selectively targeted for degradation by the direct recruitment of the autophagy protein LC3. BNIP3 and/or BNIP3L are upregulated situationally, for example during hypoxia and developmentally during erythrocyte maturation. However, it is not well understood how they are spatially regulated within the mitochondrial network to locally trigger mitophagy. Here, we find that the poorly characterized mitochondrial protein TMEM11 forms a complex with BNIP3 and BNIP3L and co-enriches at sites of mitophagosome formation. We find that mitophagy is hyper-active in the absence of TMEM11 during both normoxia and hypoxia-mimetic conditions due to an increase in BNIP3/BNIP3L mitophagy sites, supporting a model that TMEM11 spatially restricts mitophagosome formation.
    DOI:  https://doi.org/10.1083/jcb.202204021
  18. Immunity. 2023 Feb 14. pii: S1074-7613(23)00014-6. [Epub ahead of print]56(2): 240-255
    Principles of regulatory T cell function.
    Stanislav Dikiy, Alexander Y Rudensky.
      Regulatory T (Treg) cells represent a distinct lineage of cells of the adaptive immune system indispensable for forestalling fatal autoimmune and inflammatory pathologies. The role of Treg cells as principal guardians of the immune system can be attributed to their ability to restrain all currently recognized major types of inflammatory responses through modulating the activity of a wide range of cells of the innate and adaptive immune system. This broad purview over immunity and inflammation is afforded by the multiple modes of action Treg cells exert upon their diverse molecular and cellular targets. Beyond the suppression of autoimmunity for which they were originally recognized, Treg cells have been implicated in tissue maintenance, repair, and regeneration under physiologic and pathologic conditions. Herein, we discuss the current and emerging understanding of Treg cell effector mechanisms in the context of the basic properties of Treg cells that endow them with such functional versatility.
    Keywords:  immune regulation; immune suppression; regulatory T cells
    DOI:  https://doi.org/10.1016/j.immuni.2023.01.004
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