bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022–12–18
twenty papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. IRF2 integrates inflammatory signals to balance T cell exhaustion.
  2. Aging-associated HELIOS deficiency in naive CD4+ T cells alters chromatin remodeling and promotes effector cell responses.
  3. Metabolic modulation of transcription: The role of one-carbon metabolism.
  4. Targeting lactate metabolism for cancer immunotherapy - a matter of precision.
  5. Differential expression of CD8 defines phenotypically distinct cytotoxic T cells in cancer and multiple sclerosis.
  6. Roquin-dependent gene regulation in immune-mediated diseases and future therapies.
  7. Enrichment of T-cell proliferation and memory gene signatures of CD79A/CD40 costimulatory domain potentiates CD19CAR-T cell functions.
  8. Endogenous drivers of altered immune cell metabolism.
  9. A selective LIS1 requirement for mitotic spindle assembly discriminates distinct T-cell division mechanisms within the T-cell lineage.
  10. Engineering amino acid uptake or catabolism promotes CAR-T cell adaption to the tumour environment.
  11. cBAF and MYC: decision makers for T cell memory differentiation.
  12. NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy.
  13. Methods to Assess the Role of PARPs in Regulating Mitochondrial Oxidative Function.
  14. Targeting AMPK signaling by polyphenols: a novel strategy for tackling aging.
  15. LDHA: The Obstacle to T cell responses against tumor.
  16. Isolation of adoptively transferred CD8+ T cells in mouse tumor tissues for lipid peroxidation detection.
  17. cAMP agonist forskolin disrupts mitochondrial metabolism and induces senescence in human mesenchymal cells.
  18. 89ZED88082A Safely Characterizes Whole-Body CD8+ T-cell Distribution.
  19. Expression of inducible factors reprograms CAR-T cells for enhanced function and safety.
  20. Characterization of pathogenic synovial IL-17A-producing CD8+ T cell subsets in collagen-induced arthritis.
  1. Immunity. 2022 Dec 13. pii: S1074-7613(22)00600-8. [Epub ahead of print]55(12): 2225-2227
    IRF2 integrates inflammatory signals to balance T cell exhaustion.
    Amania A Sheikh, Daniel T Utzschneider.
      The transcription factor interferon regulatory factor 2 (IRF2) translates interferon signaling to regulate T cells. In this issue of Immunity, Lukhele et al. identify IRF2 in tumor-infiltrating T cells as a sensor for extrinsic signals that drives an exhaustion program.
    DOI:  https://doi.org/10.1016/j.immuni.2022.11.010
  2. Nat Immunol. 2022 Dec 12.
    Aging-associated HELIOS deficiency in naive CD4+ T cells alters chromatin remodeling and promotes effector cell responses.
    Huimin Zhang, Rohit R Jadhav, Wenqiang Cao, Isabel N Goronzy, Tuantuan V Zhao, Jun Jin, Shozo Ohtsuki, Zhaolan Hu, Jose Morales, William J Greenleaf, Cornelia M Weyand, Jörg J Goronzy.
      Immune aging combines cellular defects in adaptive immunity with the activation of pathways causing a low-inflammatory state. Here we examined the influence of age on the kinetic changes in the epigenomic and transcriptional landscape induced by T cell receptor (TCR) stimulation in naive CD4+ T cells. Despite attenuated TCR signaling in older adults, TCR activation accelerated remodeling of the epigenome and induced transcription factor networks favoring effector cell differentiation. We identified increased phosphorylation of STAT5, at least in part due to aberrant IL-2 receptor and lower HELIOS expression, as upstream regulators. Human HELIOS-deficient, naive CD4+ T cells, when transferred into human-synovium-mouse chimeras, infiltrated tissues more efficiently. Inhibition of IL-2 or STAT5 activity in T cell responses of older adults restored the epigenetic response pattern to the one seen in young adults. In summary, reduced HELIOS expression in non-regulatory naive CD4+ T cells in older adults directs T cell fate decisions toward inflammatory effector cells that infiltrate tissue.
    DOI:  https://doi.org/10.1038/s41590-022-01369-x
  3. Cell Chem Biol. 2022 Dec 01. pii: S2451-9456(22)00415-9. [Epub ahead of print]
    Metabolic modulation of transcription: The role of one-carbon metabolism.
    Jung-Ming G Lin, Savvas Kourtis, Ritobrata Ghose, Natalia Pardo Lorente, Stefan Kubicek, Sara Sdelci.
      While it is well known that expression levels of metabolic enzymes regulate the metabolic state of the cell, there is mounting evidence that the converse is also true, that metabolite levels themselves can modulate gene expression via epigenetic modifications and transcriptional regulation. Here we focus on the one-carbon metabolic pathway, which provides the essential building blocks of many classes of biomolecules, including purine nucleotides, thymidylate, serine, and methionine. We review the epigenetic roles of one-carbon metabolic enzymes and their associated metabolites and introduce an interactive computational resource that places enzyme essentiality in the context of metabolic pathway topology. Therefore, we briefly discuss examples of metabolic condensates and higher-order complexes of metabolic enzymes downstream of one-carbon metabolism. We speculate that they may be required to the formation of transcriptional condensates and gene expression control. Finally, we discuss new ways to exploit metabolic pathway compartmentalization to selectively target these enzymes in cancer.
    Keywords:  cancer; chromatin; epigenetics; folate metabolism; metabolic condensates; nuclear condensates; nuclear metabolism; nucleotides; one-carbon metabolism; phase separation; purinergic signaling; transcription regulation; transcriptional condensates
    DOI:  https://doi.org/10.1016/j.chembiol.2022.11.009
  4. Semin Cancer Biol. 2022 Dec 07. pii: S1044-579X(22)00255-3. [Epub ahead of print]88 32-45
    Targeting lactate metabolism for cancer immunotherapy - a matter of precision.
    Christoph Heuser, Kathrin Renner, Marina Kreutz, Luca Gattinoni.
      Immune checkpoint inhibitors and adoptive T cell therapies have been valuable additions to the toolbox in the fight against cancer. These treatments have profoundly increased the number of patients with a realistic perspective toward a return to a cancer-free life. Yet, in a number of patients and tumor entities, cancer immunotherapies have been ineffective so far. In solid tumors, immune exclusion and the immunosuppressive tumor microenvironment represent substantial roadblocks to successful therapeutic outcomes. A major contributing factor to the depressed anti-tumor activity of immune cells in tumors is the harsh metabolic environment. Hypoxia, nutrient competition with tumor and stromal cells, and accumulating noxious waste products, including lactic acid, pose massive constraints to anti-tumor immune cells. Numerous strategies are being developed to exploit the metabolic vulnerabilities of tumor cells in the hope that these would also alleviate metabolism-inflicted immune suppression. While promising in principle, especially in combination with immunotherapies, these strategies need to be scrutinized for their effect on tumor-fighting immune cells, which share some of their key metabolic properties with tumor cells. Here, we provide an overview of strategies that seek to tackle lactate metabolism in tumor or immune cells to unleash anti-tumor immune responses, thereby opening therapeutic options for patients whose tumors are currently not treatable.
    Keywords:  Acidification; Adoptive cell transfer; Checkpoint inhibition; Glycolysis; Immunotherapy; Lactate; Metabolism
    DOI:  https://doi.org/10.1016/j.semcancer.2022.12.001
  5. Clin Transl Med. 2022 Dec;12(12): e1068
    Differential expression of CD8 defines phenotypically distinct cytotoxic T cells in cancer and multiple sclerosis.
    Tobias Burkard, Martina Herrero San Juan, Caroline Dreis, Anastasiia Kiprina, Dmitry Namgaladze, Kai Siebenbrodt, Sebastian Luger, Christian Foerch, Josef M Pfeilschifter, Andreas Weigert, Heinfried H Radeke.
       BACKGROUND: Cytotoxic T lymphocytes take on a leading role in many immune-related diseases. They function as key effector immune cells fighting cancer cells, but they are also considerably involved in autoimmune diseases. Common to both situations, CD8+ T cells need to adapt their metabolism and effector function to the harsh and nutrient-deprived conditions of the disease-associated microenvironment.
    METHODS: We used an in vitro starvation as well as rapamycin treatment protocol mimicking nutrient deprivation to generate CD8Low versus CD8High T cells and performed FACS-Sorting followed by transcriptomic profiling of the cytotoxic T cell subsets. Prominent markers identified in the CD8Low versus the CD8High T cells were then used to investigate the presence of these cell subsets in immune-related human diseases. Employing cancer tissue microarrays and PhenOptics multispectral imaging as well as flow cytometry, we studied these CD8+ T cell subsets in cancer and relapsing-remitting multiple sclerosis patients.
    RESULTS: Starvation induced a decreased expression of CD8, yielding a CD8Low T cell subpopulation with an altered transcriptomic signature and reduced effector function. CD8Low T cell showed enhanced ST2L and IL6ST (CD130) expression compared to CD8High T cells which expressed elevated KLRD1 (CD94) and granzyme B levels within the tumour microenvironment (TME). Spatial analysis revealed the presence of CD8High T cells in close proximity to tumour cells, while the CD8Low T cells resided at the tumour boundaries. Importantly, the number of tumour-infiltrating CD8Low T lymphocytes correlated with a poor prognosis as well as with enhanced cancer progression in human mammary carcinoma. We also found a reduced frequency of CD8Low T lymphocytes in a cohort of relapse (disease active) multiple sclerosis patients compared to healthy subjects during immune cell starvation in vitro.
    CONCLUSIONS: In summary, our data show that functionally distinct cytotoxic T lymphocytes can be identified based on their expression of CD8. Indicating a more general role in CD8 T cell immunity, these cells may play opposing roles in the TME, and also in the pathophysiology of autoimmune diseases such as multiple sclerosis.
    Keywords:  CD8+ T cells; mTOR; multiple sclerosis; multispectral imaging; tumour immunity
    DOI:  https://doi.org/10.1002/ctm2.1068
  6. Int Immunol. 2022 Dec 16. pii: dxac059. [Epub ahead of print]
    Roquin-dependent gene regulation in immune-mediated diseases and future therapies.
    Timsse Raj, Arlinda Negraschus, Vigo Heissmeyer.
      The RNA-binding proteins Roquin-1/2 and Regnase-1 exert essential regulation by controlling proinflammatory mRNA expression to prevent autoimmune disease. More recently, inhibition of this post-transcriptional gene regulatory program has been demonstrated to enable enhanced anti-tumor responses by tumor antigen-specific CD8 + T cells. In this review we describe the functions of these RNA-binding proteins and the phenotypes that arise in association with genetic inhibition or inactivation. We discuss how inducible inactivation of the system reprograms CD4 + and CD8 + T cell fates by changing cell metabolism, activation, differentiation or effector/memory decisions. We furthermore outline what we need to know to precisely modulate this system in order to dampen autoimmune reactions or boost the efficacy of adoptively transferred T cells or chimeric antigen receptor (CAR) T cells in cancer immunotherapies.
    Keywords:  Regnase-1; autoimmunity; autoinflammation; cancer therapy; post-transcriptional gene regulation
    DOI:  https://doi.org/10.1093/intimm/dxac059
  7. Front Immunol. 2022 ;13 1064339
    Enrichment of T-cell proliferation and memory gene signatures of CD79A/CD40 costimulatory domain potentiates CD19CAR-T cell functions.
    Socheatraksmey Ung, Pongsakorn Choochuen, Wannakorn Khopanlert, Kajornkiat Maneechai, Surasak Sangkhathat, Seitaro Terakura, Jakrawadee Julamanee.
      CD19 chimeric antigen receptor (CAR) T-cells have demonstrated remarkable outcomes in B-cell malignancies. Recently, the novel CD19CAR-T cells incorporated with B-cell costimulatory molecules of CD79A/CD40 demonstrated superior antitumor activity in the B-cell lymphoma model compared with CD28 or 4-1BB. Here, we investigated the intrinsic transcriptional gene underlying the functional advantage of CD19.79A.40z CAR-T cells following CD19 antigen exposure using transcriptome analysis compared to CD28 or 4-1BB. Notably, CD19.79A.40z CAR-T cells up-regulated genes involved in T-cell activation, T-cell proliferation, and NF-κB signaling, whereas down-regulated genes associated with T-cell exhaustion and apoptosis. Interestingly, CD19.79A.40z CAR- and CD19.BBz CAR-T cells were enriched in almost similar pathways. Furthermore, gene set enrichment analysis demonstrated the enrichment of genes, which were previously identified to correlate with T-cell proliferation, interferon signaling pathway, and naïve and memory T-cell signatures, and down-regulated T-cell exhaustion genes in CD79A/CD40, compared with the T-cell costimulatory domain. The CD19.79A.40z CAR-T cells also up-regulated genes related to glycolysis and fatty acid metabolism, which are necessary to drive T-cell proliferation and differentiation compared with conventional CD19CAR-T cells. Our study provides a comprehensive insight into the understanding of gene signatures that potentiates the superior antitumor functions by CD19CAR-T cells incorporated with the CD79A/CD40 costimulatory domain.
    Keywords:  CAR-T cell; CD19; CD79A/CD40; costimulatory domain; gene expression profiling
    DOI:  https://doi.org/10.3389/fimmu.2022.1064339
  8. Exp Biol Med (Maywood). 2022 Dec 13. 15353702221134093
    Endogenous drivers of altered immune cell metabolism.
    Lianne C Shanley, Hannah K Fitzgerald, Sinead A O'Rourke, Aisling Dunne.
      Dysregulated metabolism has long been recognized as a feature of many metabolic disorders. However, recent studies demonstrating that metabolic reprogramming occurs in immune cells have led to a growing interest in the relationship between metabolic rewiring and immune-mediated disease pathogeneses. It is clear now that immune cell subsets engage in different metabolic pathways depending on their activation and/or maturation state. As a result, it may be possible to modulate metabolic reprogramming for clinical benefit. In this review, we provide an overview of immune cell metabolism with focus on endogenous drivers of metabolic reprogramming given their link to a number of immune-mediated disorders.
    Keywords:  Immunometabolism; cellular respiration; damage or disease-associated molecular patterns; metabolic reprogramming
    DOI:  https://doi.org/10.1177/15353702221134093
  9. Elife. 2022 Dec 15. pii: e80277. [Epub ahead of print]11
    A selective LIS1 requirement for mitotic spindle assembly discriminates distinct T-cell division mechanisms within the T-cell lineage.
    Jérémy Argenty, Nelly Rouquié, Cyrielle Bories, Suzanne Mélique, Valérie Duplan-Eche, Abdelhadi Saoudi, Nicolas Fazilleau, Renaud Lesourne.
      The ability to proliferate is a common feature of most T-cell populations. However, proliferation follows different cell-cycle dynamics and is coupled to different functional outcomes according to T-cell subsets. Whether the mitotic machineries supporting these qualitatively distinct proliferative responses are identical remains unknown. Here, we show that disruption of the microtubule-associated protein LIS1 in mouse models leads to proliferative defects associated with a blockade of T-cell development after b-selection and of peripheral CD4+ T cell expansion after antigen priming. In contrast, cell divisions in CD8+ T cells occurred independently of LIS1 following T-cell antigen receptor stimulation, although LIS1 was required for proliferation elicited by pharmacological activation. In thymocytes and CD4+ T cells, LIS1-deficiency did not affect signaling events leading to activation but led to an interruption of proliferation after the initial round of division and to p53-induced cell death. Proliferative defects resulted from a mitotic failure, characterized by the presence of extra-centrosomes and the formation of multipolar spindles, causing abnormal chromosomes congression during metaphase and separation during telophase. LIS1 was required to stabilize dynein/dynactin complexes, which promote chromosome attachment to mitotic spindles and ensure centrosome integrity. Together, these results suggest that proliferative responses are supported by distinct mitotic machineries across T-cell subsets.
    Keywords:  cell biology; immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.80277
  10. Blood Adv. 2022 Dec 15. pii: bloodadvances.2022008272. [Epub ahead of print]
    Engineering amino acid uptake or catabolism promotes CAR-T cell adaption to the tumour environment.
    Silvia Panetti, Nicola Jane McJannett, Livingstone Fultang, Sarah Booth, Luciana Gneo, Ugo Scarpa, Charles Smith, Ashley Vardon, Lisa Vettore, Celina Whalley, Yi Pan, Csilla Varnai, Hitoshi Endou, Jonathan Barlow, Daniel A Tennant, Andrew D Beggs, Francis Jay Mussai, Carmela De Santo.
      Cancer cells take up amino acids from the extracellular space to drive cell proliferation and viability. Similar mechanisms are employed by immune cells. The result is competition between conventional T cells, or indeed CAR-T cells, and tumour cells for limited availability of amino acids within the environment. We demonstrate that T cells can be re-engineered to express SLC7A5 or SLC7A11 transmembrane amino acid transporters alongside chimeric antigen receptors (CAR). Transporter modifications increase CAR-T cell proliferation under low tryptophan or cystine conditions with no loss of CAR cytotoxicity or increased exhaustion. Transcriptomic and phenotypic analysis reveals that downstream, SLC7A5/SLC7A11 modified CAR-T cells upregulate intracellular Arginase expression and activity. In turn we engineer and phenotype a further generation of CAR-T cells which express functional Arginase I/Arginase II enzymes, and have enhanced CAR-T cell proliferation and anti-tumour activity. Thus CAR-T cells can be adapted to the amino acid metabolic microenvironment of cancer, a hitherto recognised but unaddressed barrier to successful CAR-T therapy.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008272
  11. Signal Transduct Target Ther. 2022 Dec 12. 7(1): 389
    cBAF and MYC: decision makers for T cell memory differentiation.
    Kaili Ma, Hongcheng Cheng, Lianjun Zhang.
      
    DOI:  https://doi.org/10.1038/s41392-022-01238-x
  12. EMBO J. 2022 Dec 14. e111372
    NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy.
    Tetsushi Kataura, Elsje G Otten, Yoana Rabanal-Ruiz, Elias Adriaenssens, Francesca Urselli, Filippo Scialo, Lanyu Fan, Graham R Smith, William M Dawson, Xingxiang Chen, Wyatt W Yue, Agnieszka K Bronowska, Bernadette Carroll, Sascha Martens, Michael Lazarou, Viktor I Korolchuk.
      Mitophagy, the elimination of mitochondria via the autophagy-lysosome pathway, is essential for the maintenance of cellular homeostasis. The best characterised mitophagy pathway is mediated by stabilisation of the protein kinase PINK1 and recruitment of the ubiquitin ligase Parkin to damaged mitochondria. Ubiquitinated mitochondrial surface proteins are recognised by autophagy receptors including NDP52 which initiate the formation of an autophagic vesicle around the mitochondria. Damaged mitochondria also generate reactive oxygen species (ROS) which have been proposed to act as a signal for mitophagy, however the mechanism of ROS sensing is unknown. Here we found that oxidation of NDP52 is essential for the efficient PINK1/Parkin-dependent mitophagy. We identified redox-sensitive cysteine residues involved in disulphide bond formation and oligomerisation of NDP52 on damaged mitochondria. Oligomerisation of NDP52 facilitates the recruitment of autophagy machinery for rapid mitochondrial degradation. We propose that redox sensing by NDP52 allows mitophagy to function as a mechanism of oxidative stress response.
    Keywords:  NDP52; autophagy; mitophagy; p62; redox
    DOI:  https://doi.org/10.15252/embj.2022111372
  13. Methods Mol Biol. 2023 ;2609 227-249
    Methods to Assess the Role of PARPs in Regulating Mitochondrial Oxidative Function.
    Tünde Kovács, Boglárka Rauch, Edit Mikó, Péter Bai.
      PARP enzymes are involved in metabolic regulation and impact on a plethora of cellular metabolic pathways, among them, mitochondrial oxidative metabolism. The detrimental effects of PARP1 overactivation upon oxidative stress on mitochondrial oxidative metabolism was discovered in 1998. Since then, there was an enormous blooming in the understanding of the interplay between PARPs and mitochondria. Mitochondrial activity can be assessed by a comprehensive set of methods that we aim to introduce here.
    Keywords:  ARTD; Differentiation; Flow cytometry; Mitochondria; Mitochondrial fission; Mitochondrial fusion; Mitochondrial morphology; Oximetry; PARP; Seahorse extracellular flux analyzer; Substrate preference; Δψ
    DOI:  https://doi.org/10.1007/978-1-0716-2891-1_14
  14. Food Funct. 2022 Dec 16.
    Targeting AMPK signaling by polyphenols: a novel strategy for tackling aging.
    Wei Xu, Yi Luo, Jiaxin Yin, Mengzhen Huang, Feijun Luo.
      Aging is an inevitable biological process and is accompanied by a gradual decline of physiological functions, such as the incidence of age-related diseases. Aging becomes a major burden and challenge for society to prevent or delay the occurrence and development of these age-related diseases. AMPK is a key regulator of intracellular energy and participates in the adaptation of calorie restriction. It is also an important mediator of nutritionally sensitive pathways that regulate the biological effects of nutrient active ingredients. AMPK can limit proliferation and activate autophagy. Recent studies have shown that nutritional intervention can delay aging and lessen age-related diseases in many animal and even human models. Polyphenols function as a natural antidote and are important anti-inflammatory and antioxidant agents in human diets. Polyphenols can prevent age-related diseases because they regulate complex networks of cellular processes such as oxidative damage, inflammation, cellular aging, and autophagy, and have also attracted wide attention as a potential beneficial substance for longevity. In this review, we systemically summarized the progress of targeting AMPK signaling by dietary polyphenols in aging prevention. Polyphenols can reduce oxidative stress and inflammatory response, and maintain the steady state of energy. Polyphenols can also modulate sirtuins/NAD+, nutrient-sensing, proteostasis, mitochondrial function, autophagy and senescence via targeting AMPK signaling. Therefore, targeting the AMPK signaling pathway by dietary polyphenols may be a novel anti-aging strategy.
    DOI:  https://doi.org/10.1039/d2fo02688k
  15. Front Oncol. 2022 ;12 1036477
    LDHA: The Obstacle to T cell responses against tumor.
    Yu Tang, Shuangshuang Gu, Liqun Zhu, Yujiao Wu, Wei Zhang, Chuanxiang Zhao.
      Immunotherapy has become a successful therapeutic strategy in certain solid tumors and hematological malignancies. However, this efficacy of immunotherapy is impeded by limited success rates. Cellular metabolic reprogramming determines the functionality and viability in both cancer cells and immune cells. Extensive research has unraveled that the limited success of immunotherapy is related to immune evasive metabolic reprogramming in tumor cells and immune cells. As an enzyme that catalyzes the final step of glycolysis, lactate dehydrogenase A (LDHA) has become a major focus of research. Here, we have addressed the structure, localization, and biological features of LDHA. Furthermore, we have discussed the various aspects of epigenetic regulation of LDHA expression, such as histone modification, DNA methylation, N6-methyladenosine (m6A) RNA methylation, and transcriptional control by noncoding RNA. With a focus on the extrinsic (tumor cells) and intrinsic (T cells) functions of LDHA in T-cell responses against tumors, in this article, we have reviewed the current status of LDHA inhibitors and their combination with T cell-mediated immunotherapies and postulated different strategies for future therapeutic regimens.
    Keywords:  LDHA; T cell responses; lactate; metabolic reprogramming; tumor
    DOI:  https://doi.org/10.3389/fonc.2022.1036477
  16. STAR Protoc. 2022 Dec 15. pii: S2666-1667(22)00825-5. [Epub ahead of print]4(1): 101945
    Isolation of adoptively transferred CD8+ T cells in mouse tumor tissues for lipid peroxidation detection.
    Liuling Xiao, Qing Yi.
      The lipid peroxidation level of tumor-infiltrating CD8+ T cells is crucial for its activity and longevity. Here, we describe a protocol for effective and epitope-preserving dissociation of mouse tumors and subsequent leukocyte purification and lipid peroxidation staining of adoptively transferred CD8+ T cells. We use BODIPY 581/591 C11 to monitor the cellular lipid peroxidation level and detect its fluorescent change by flow cytometry, followed by analysis in FlowJo. This protocol is adaptable to intrinsic CD8+ T cells in tumors as well. For complete details on the use and execution of this protocol, please refer to Xiao et al. (2022)1 and Ma et al. (2021).2.
    Keywords:  Cancer; Cell Biology; Flow Cytometry/Mass Cytometry; Immunology; Metabolism; Molecular/Chemical Probes; Single Cell
    DOI:  https://doi.org/10.1016/j.xpro.2022.101945
  17. Stem Cells Dev. 2022 Dec 11.
    cAMP agonist forskolin disrupts mitochondrial metabolism and induces senescence in human mesenchymal cells.
    Qiaoling Wang, Xiaodong Su, Rongjia Zhu, Robert Chunhua Zhao.
      Adult-derived mesenchymal stem cells (MSCs) can be used in therapies for the treatment of various diseases. MSCs derived from aging tissues or long-term MSC cultures could have diminished therapeutic effects compared with MSCs derived from younger tissues, but the underlying mechanism has not been completely established. Dysfunction of energy metabolism is one of the main mechanisms underlying cell senescence. Although cyclic adenosine monophosphate (cAMP) is known to inhibit cell division and proliferation in vitro, its impact on MSC senescence has not been described. In this study, we used forskolin, an adenylate cyclase agonist and cAMP inducer, to disrupt metabolism in human adipose-derived MSCs and investigate the effects of metabolic dysfunction on MSC senescence. Treatment of human MSCs with forskolin resulted in senescence phenotypes, including reduced proliferation, cell-cycle arrest, and enhanced expression of the cell aging markers p16 and p21. Furthermore, the senescent MSCs exhibited increased adipogenesis capacity and decreased osteogenesis capacity as well as a senescence-associated secretory phenotype characterized by increased expression of several inflammatory factors. Forskolin-associated MSC senescence was mainly caused by oxidative stress-induced disruption of mitochondrial metabolism, and the senescent MSCs had high levels of reactive oxygen species and reduced sirtuin gene expression. Lastly, we found that cAMP inhibitor SQ22536 protects MSCs from forskolin-induced senescence and senescence-related-inflammatory-phenotype (SASP). Our results indicate that forskolin can cause senescence of human MSCs through oxidative stress-induced mitochondrial metabolic dysfunction, and thus the results provide a basis for developing strategies for improving the quality and efficacy of cultured MSCs for clinical use.
    DOI:  https://doi.org/10.1089/scd.2022.0180
  18. Cancer Discov. 2022 Dec 16. OF1
    89ZED88082A Safely Characterizes Whole-Body CD8+ T-cell Distribution.
      The 89ZED88082A antibody tracer allows for imaging of the whole-body distribution of CD8+ T cells.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-221
  19. Cancer Cell. 2022 Dec 12. pii: S1535-6108(22)00553-0. [Epub ahead of print]40(12): 1470-1487.e7
    Expression of inducible factors reprograms CAR-T cells for enhanced function and safety.
    Anže Smole, Alexander Benton, Mathilde A Poussin, Monika A Eiva, Claudia Mezzanotte, Barbara Camisa, Beatrice Greco, Prannda Sharma, Nicholas G Minutolo, Falon Gray, Adham S Bear, Miren L Baroja, Casey Cummins, Chong Xu, Francesca Sanvito, Andrea Lang Goldgewicht, Tatiana Blanchard, Alba Rodriguez-Garcia, Michael Klichinsky, Chiara Bonini, Carl H June, Avery D Posey, Gerald P Linette, Beatriz M Carreno, Monica Casucci, Daniel J Powell.
      Despite the success of CAR-T cell cancer immunotherapy, challenges in efficacy and safety remain. Investigators have begun to enhance CAR-T cells with the expression of accessory molecules to address these challenges. Current systems rely on constitutive transgene expression or multiple viral vectors, resulting in unregulated response and product heterogeneity. Here, we develop a genetic platform that combines autonomous antigen-induced production of an accessory molecule with constitutive CAR expression in a single lentiviral vector called Uni-Vect. The broad therapeutic application of Uni-Vect is demonstrated in vivo by activation-dependent expression of (1) an immunostimulatory cytokine that improves efficacy, (2) an antibody that ameliorates cytokine-release syndrome, and (3) transcription factors that modulate T cell biology. Uni-Vect is also implemented as a platform to characterize immune receptors. Overall, we demonstrate that Uni-Vect provides a foundation for a more clinically actionable next-generation cellular immunotherapy.
    Keywords:  CAR-T Cells; CRS; IL-12; IL-6; NFAT; TCR; armored; inducible; single lentiviral expression system; transcription factor
    DOI:  https://doi.org/10.1016/j.ccell.2022.11.006
  20. Cell Immunol. 2022 Dec 10. pii: S0008-8749(22)00180-0. [Epub ahead of print]383 104655
    Characterization of pathogenic synovial IL-17A-producing CD8+ T cell subsets in collagen-induced arthritis.
    Song Zhang, Yanbo Zhou, Pu Yang, Shuo Jia, Cheng Peng, Haiqing Hu, Wei Liu.
      Using a murine collagen-induced arthritis model, we characterized the heterogeneity of synovial CD8+ T cells based on the expression of chemokine receptors, cytokines, and nuclear transcription factors. Four subsets, i.e. CXCR3-CCR4- cells, CXCR3+CCR4- cells, CXCR3+CCR4+ cells, and CXCR3-CCR4+ cells, were present in synovial CD8+CD62L-CCR6+IL-23R+CCR10- T cells. CXCR3-CCR4- cells belonged to exhausted CD8+ T cells. CXCR3+CCR4- cells were Tc17.1 cells expressing both IL-17A and IFN-γ. CXCR3+CCR4+ cells were transitional Tc17.1 cells expressing IL-17A but lower IFN-γ, and CXCR3-CCR4+ cells were Tc17 cells expressing IL-17A but no IFN-γ. Transitional Tc17.1 cells can differentiate into Tc17.1 cells in vitro under the instruction of IL-12. Tc17.1 cells and transitional Tc17.1 cells strongly induced the expression of pro-inflammatory mediators in synovial fibroblasts, whereas Tc17 cells were less potent in doing so. IFN-γ was involved in the higher pathogenicity of Tc17.1 cells and transitional Tc17.1 cells on synovial fibroblasts. This study expands the understanding of Tc17 biology by unveiling the phenotypic and functional heterogeneity of synovial IL-17A-expressing CD8+ T cells. These heterogeneous IL-17A-expressing CD8+ T cells could be novel therapeutic targets in future arthritis treatment.
    Keywords:  Arthritis; Inflammation; Interferon-γ; Interleukin-17A; Tc17 cells
    DOI:  https://doi.org/10.1016/j.cellimm.2022.104655
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