bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022–08–21
nineteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Carbon source availability drives nutrient utilization in CD8+ T cells.
  2. TCR-independent metabolic reprogramming precedes lymphoma-driven changes in T-cell fate.
  3. Succinate uptake by T cells suppresses their effector function via inhibition of mitochondrial glucose oxidation.
  4. T cell senescence by N-glycan branching.
  5. MYB orchestrates T cell exhaustion and response to checkpoint inhibition.
  6. Signaling networks controlling ID and E protein activity in T cell differentiation and function.
  7. PYGBacking on glycogen metabolism to fuel early memory T cell recall responses.
  8. Metabolic alterations impair differentiation and effector functions of CD8+ T cells.
  9. UBXD8 mediates mitochondria-associated degradation to restrain apoptosis and mitophagy.
  10. Principles of reproducible metabolite profiling of enriched lymphocytes in tumors and ascites from human ovarian cancer.
  11. Metabolic analyses reveal dysregulated NAD+ metabolism and altered mitochondrial state in ulcerative colitis.
  12. TGF-β regulates the stem-like state of PD-1+ TCF-1+ virus-specific CD8 T cells during chronic infection.
  13. NF-κB: blending metabolism, immunity, and inflammation.
  14. A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues.
  15. Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells.
  16. CRISPRi-mediated knock-down of PRDM1/BLIMP1 programs central memory differentiation in ex vivo-expanded human T cells.
  17. Glucose transport in the regulation of T-cell activation: the journey may be as important as the destination.
  18. TGF-β promotes stem-like T cells via enforcing their lymphoid tissue retention.
  19. A protocol for rapid construction of senescent cells.
  1. Cell Metab. 2022 Aug 11. pii: S1550-4131(22)00311-4. [Epub ahead of print]
    Carbon source availability drives nutrient utilization in CD8+ T cells.
    Irem Kaymak, Katarzyna M Luda, Lauren R Duimstra, Eric H Ma, Joseph Longo, Michael S Dahabieh, Brandon Faubert, Brandon M Oswald, McLane J Watson, Susan M Kitchen-Goosen, Lisa M DeCamp, Shelby E Compton, Zhen Fu, Ralph J DeBerardinis, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.
      How environmental nutrient availability impacts T cell metabolism and function remains poorly understood. Here, we report that the presence of physiologic carbon sources (PCSs) in cell culture medium broadly impacts glucose utilization by CD8+ T cells, independent of transcriptional changes in metabolic reprogramming. The presence of PCSs reduced glucose contribution to the TCA cycle and increased effector function of CD8+ T cells, with lactate directly fueling the TCA cycle. In fact, CD8+ T cells responding to Listeria infection preferentially consumed lactate over glucose as a TCA cycle substrate in vitro, with lactate enhancing T cell bioenergetic and biosynthetic capacity. Inhibiting lactate-dependent metabolism in CD8+ T cells by silencing lactate dehydrogenase A (Ldha) impaired both T cell metabolic homeostasis and proliferative expansion in vivo. Together, our data indicate that carbon source availability shapes T cell glucose metabolism and identifies lactate as a bioenergetic and biosynthetic fuel for CD8+ effector T cells.
    Keywords:  (13)C tracing; T cells; TCA cycle; immunometabolism; lactate; metabolic programming; metabolomics
    DOI:  https://doi.org/10.1016/j.cmet.2022.07.012
  2. Cancer Immunol Res. 2022 Aug 15. pii: CIR-21-0813. [Epub ahead of print]
    TCR-independent metabolic reprogramming precedes lymphoma-driven changes in T-cell fate.
    Rebecca S Hesterberg, Min Liu, Aya G Elmarsafawi, John M Koomen, Eric A Welsh, Stephen G Hesterberg, Sujeewa Ranatunga, Chunying Yang, Weimin Li, Harshani R Lawrence, Paulo C Rodriguez, Anders E Berglund, John L Cleveland.
      Chronic T-cell receptor (TCR) signaling in the tumor microenvironment is known to promote T-cell dysfunction. However, we reasoned that poorly immunogenic tumors may also compromise T cells by impairing their metabolism. To address this, we assessed temporal changes in T-cell metabolism, fate, and function in models of ¬B-cell lymphoma driven by Myc, a promoter of energetics and repressor of immunogenicity. Increases in lymphoma burden most significantly impaired CD4+ T-cell function and promoted regulatory T-cell (Treg) and Th1-cell differentiation. Metabolomic analyses revealed early reprogramming of CD4+ T-cell metabolism, reduced glucose uptake, and impaired mitochondrial function, which preceded changes in T-cell fate. In contrast, B-cell lymphoma metabolism remained robust during tumor progression. Finally, mitochondrial functions were impaired in CD4+ and CD8+ T cells in lymphoma-transplanted OT-II and OT-I transgenic mice, respectively. These findings support a model, whereby early, TCR-independent, metabolic interactions with developing lymphomas limits T cell-mediated immune surveillance.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-21-0813
  3. Cell Rep. 2022 Aug 16. pii: S2211-1247(22)01010-5. [Epub ahead of print]40(7): 111193
    Succinate uptake by T cells suppresses their effector function via inhibition of mitochondrial glucose oxidation.
    Nancy Gudgeon, Haydn Munford, Emma L Bishop, James Hill, Taylor Fulton-Ward, David Bending, Jennie Roberts, Daniel A Tennant, Sarah Dimeloe.
      Succinate dehydrogenase (SDH) loss-of-function mutations drive succinate accumulation in tumor microenvironments, for example in the neuroendocrine tumors pheochromocytoma (PC) and paraganglioma (PG). Control of innate immune cell activity by succinate is described, but effects on T cells have not been interrogated. Here we report that exposure of human CD4+ and CD8+ T cells to tumor-associated succinate concentrations suppresses degranulation and cytokine secretion, including of the key anti-tumor cytokine interferon-γ (IFN-γ). Mechanistically, this is associated with succinate uptake-partly via the monocarboxylate transporter 1 (MCT1)-inhibition of succinyl coenzyme A synthetase activity and impaired glucose flux through the tricarboxylic acid cycle. Consistently, pharmacological and genetic interventions restoring glucose oxidation rescue T cell function. Tumor RNA-sequencing data from patients with PC and PG reveal profound suppression of IFN-γ-induced genes in SDH-deficient tumors compared with those with other mutations, supporting a role for succinate in modulating the anti-tumor immune response in vivo.
    Keywords:  CP: immunology; CP: metabolism; T cell; metabolism; metabolite; succinate; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2022.111193
  4. Aging (Albany NY). 2022 Aug 13. undefined(undefined):
    T cell senescence by N-glycan branching.
    Haik Mkhikian, Michael Demetriou.
      
    Keywords:  N-acetylglucosamine; N-glycan branching; T cell; immune-senescence; interleukin-7
    DOI:  https://doi.org/10.18632/aging.204239
  5. Nature. 2022 Aug 17.
    MYB orchestrates T cell exhaustion and response to checkpoint inhibition.
    Carlson Tsui, Lorenz Kretschmer, Svenja Rapelius, Sarah S Gabriel, David Chisanga, Konrad Knöpper, Daniel T Utzschneider, Simone Nüssing, Yang Liao, Teisha Mason, Santiago Valle Torres, Stephen A Wilcox, Krystian Kanev, Sebastian Jarosch, Justin Leube, Stephen L Nutt, Dietmar Zehn, Ian A Parish, Wolfgang Kastenmüller, Wei Shi, Veit R Buchholz, Axel Kallies.
      CD8+ T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality-which is referred to as T cell exhaustion1,2-is maintained by precursors of exhausted T (TPEX) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1- exhausted effector T cells3-6. Here we show that the long-term proliferative potential, multipotency and repopulation capacity of exhausted T cells during chronic infection are selectively preserved in a small population of transcriptionally distinct CD62L+ TPEX cells. The transcription factor MYB is not only essential for the development of CD62L+ TPEX cells and maintenance of the antiviral CD8+ T cell response, but also induces functional exhaustion and thereby prevents lethal immunopathology. Furthermore, the proliferative burst in response to PD-1 checkpoint inhibition originates exclusively from CD62L+ TPEX cells and depends on MYB. Our findings identify CD62L+ TPEX cells as a stem-like population that is central to the maintenance of long-term antiviral immunity and responsiveness to immunotherapy. Moreover, they show that MYB is a transcriptional orchestrator of two fundamental aspects of exhausted T cell responses: the downregulation of effector function and the long-term preservation of self-renewal capacity.
    DOI:  https://doi.org/10.1038/s41586-022-05105-1
  6. Front Immunol. 2022 ;13 964581
    Signaling networks controlling ID and E protein activity in T cell differentiation and function.
    Sung-Min Hwang, Sin-Hyeog Im, Dipayan Rudra.
      E and inhibitor of DNA binding (ID) proteins are involved in various cellular developmental processes and effector activities in T cells. Recent findings indicate that E and ID proteins are not only responsible for regulating thymic T cell development but also modulate the differentiation, function, and fate of peripheral T cells in multiple immune compartments. Based on the well-established E and ID protein axis (E-ID axis), it has been recognized that ID proteins interfere with the dimerization of E proteins, thus restricting their transcriptional activities. Given this close molecular relationship, the extent of expression or stability of these two protein families can dynamically affect the expression of specific target genes involved in multiple aspects of T cell biology. Therefore, it is essential to understand the endogenous proteins or extrinsic signaling pathways that can influence the dynamics of the E-ID axis in a cell-specific and context-dependent manner. Here, we provide an overview of E and ID proteins and the functional outcomes of the E-ID axis in the activation and function of multiple peripheral T cell subsets, including effector and memory T cell populations. Further, we review the mechanisms by which endogenous proteins and signaling pathways alter the E-ID axis in various T cell subsets influencing T cell function and fate at steady-state and in pathological settings. A comprehensive understanding of the functions of E and ID proteins in T cell biology can be instrumental in T cell-specific targeting of the E-ID axis to develop novel therapeutic modalities in the context of autoimmunity and cancer.
    Keywords:  E proteins; E-ID axis; ID proteins; T cell differentiation; T cell function; regulatory T (Treg) cells; signaling pathways
    DOI:  https://doi.org/10.3389/fimmu.2022.964581
  7. Mol Cell. 2022 Aug 18. pii: S1097-2765(22)00712-2. [Epub ahead of print]82(16): 2918-2921
    PYGBacking on glycogen metabolism to fuel early memory T cell recall responses.
    Joseph Longo, McLane J Watson, Matthew J Vos, Kelsey S Williams, Russell G Jones.
      Zhang et al. (2022) show that TCR signaling promotes the phosphorylation and activation of glycogen phosphorylase B (PYGB) in CD8+ memory T (Tmem) cells. PYGB-dependent glycogen mobilization provides a carbon source to support glycolysis and early Tmem cell recall responses.
    DOI:  https://doi.org/10.1016/j.molcel.2022.07.016
  8. Front Immunol. 2022 ;13 945980
    Metabolic alterations impair differentiation and effector functions of CD8+ T cells.
    Antonio Bensussen, Maria Angelica Santana, Otoniel Rodríguez-Jorge.
      CD8+ T lymphocytes are one of the main effector cells of the immune system, they protect the organism against intracellular threats such as viruses and bacteria, as well as neoplasms. It is currently well established that CD8+ T cells have distinct immune responses, given by their phenotypes Tc1, Tc2, Tc17, and TcReg. The cellular plasticity of such phenotypes depends on the presence of different combinations of cytokines in the extracellular medium. It is known that metabolic imbalances play an important role in immune response, but the precise role of metabolic disturbances on the differentiation and function of CD8+ T cells, however, has not been explored. In this work, we used a computational model to explore the potential effect of metabolic alterations such as hyperglycemia, high alcohol consumption, dyslipidemia, and diabetes on CD8+ T cell differentiation. Our model predicts that metabolic alterations preclude the effector function of all CD8+ T cell phenotypes except for TcReg cells. It also suggests that such inhibition originates from the increase of reactive oxygen species in response to metabolic stressors. Finally, we simulated the outcome of treating metabolic-inhibited CD8+ T cells with drugs targeting key molecules such as mTORC1, mTORC2, Akt, and others. We found that overstimulation of mTORC2 may restore cell differentiation and functions of all effector phenotypes, even in diabetic patients. These findings highlight the importance of our predictive model to find potential targets to strengthen immunosuppressed patients in chronic diseases, like diabetes.
    Keywords:  CD8+ T cells; ROS; alcohol consumption; diabetes; high-fat diet; mTORC2; metabolism; systems biology
    DOI:  https://doi.org/10.3389/fimmu.2022.945980
  9. EMBO Rep. 2022 Aug 18. e54859
    UBXD8 mediates mitochondria-associated degradation to restrain apoptosis and mitophagy.
    Jing Zheng, Yu Cao, Jun Yang, Hui Jiang.
      The hexameric AAA-ATPase valosin-containing protein (VCP) is essential for mitochondrial protein quality control. How VCP is recruited to mammalian mitochondria remains obscure. Here we report that UBXD8, an ER- and lipid droplet-localized VCP adaptor, also localizes to mitochondria and locally recruits VCP. UBXD8 associates with mitochondrial and ER ubiquitin E3 ligases and targets their substrates for degradation. Remarkably, both mitochondria- and ER-localized UBXD8 can degrade mitochondrial and ER substrates in cis and in trans. UBXD8 also associates with the TOM complex but is dispensable for translocation-associated degradation. UBXD8 knockout impairs the degradation of the pro-survival protein Mcl1 but surprisingly sensitizes cells to apoptosis and mitochondrial stresses. UBXD8 knockout also hyperactivates mitophagy. We identify pro-apoptotic BH3-only proteins Noxa, Bik, and Bnip3 as novel UBXD8 substrates and determine that UBXD8 inhibits apoptosis via degrading Noxa and restrains mitophagy via degrading Bnip3. Collectively, our characterizations reveal UBXD8 as the major mitochondrial adaptor of VCP and unveil its role in apoptosis and mitophagy regulation.
    Keywords:  UBXD8; VCP; apoptosis; mitochondria-associated degradation; mitophagy
    DOI:  https://doi.org/10.15252/embr.202254859
  10. Nat Protoc. 2022 Aug 19.
    Principles of reproducible metabolite profiling of enriched lymphocytes in tumors and ascites from human ovarian cancer.
    Marisa K Kilgour, Sarah MacPherson, Lauren G Zacharias, Jodi LeBlanc, Sindy Babinszky, Gabrielle Kowalchuk, Scott Parks, Ryan D Sheldon, Russell G Jones, Ralph J DeBerardinis, Phineas T Hamilton, Peter H Watson, Julian J Lum.
      Identifying metabolites and delineating their immune-regulatory contribution in the tumor microenvironment is an area of intense study. Interrogating metabolites and metabolic networks among immune cell subsets and host cells from resected tissues and fluids of human patients presents a major challenge, owing to the specialized handling of samples for downstream metabolomics. To address this, we first outline the importance of collaborating with a biobank for coordinating and streamlining workflow for point of care, sample collection, processing and cryopreservation. After specimen collection, we describe our 60-min rapid bead-based cellular enrichment method that supports metabolite analysis between T cells and tumor cells by mass spectrometry. We also describe how the metabolic data can be complemented with metabolic profiling by flow cytometry. This protocol can serve as a foundation for interrogating the metabolism of cell subsets from primary human ovarian cancer.
    DOI:  https://doi.org/10.1038/s41596-022-00729-z
  11. PLoS One. 2022 ;17(8): e0273080
    Metabolic analyses reveal dysregulated NAD+ metabolism and altered mitochondrial state in ulcerative colitis.
    Yu Hui Kang, Sarah A Tucker, Silvia F Quevedo, Aslihan Inal, Joshua R Korzenik, Marcia C Haigis.
      Ulcerative colitis (UC) is a complex, multifactorial disease driven by a dysregulated immune response against host commensal microbes. Despite rapid advances in our understanding of host genomics and transcriptomics, the metabolic changes in UC remain poorly understood. We thus sought to investigate distinguishing metabolic features of the UC colon (14 controls and 19 patients). Metabolomics analyses revealed inflammation state as the primary driver of metabolic variation rather than diagnosis, with multiple metabolites differentially regulated between inflamed and uninflamed tissues. Specifically, inflamed tissues were characterized by reduced levels of nicotinamide adenine dinucleotide (NAD+) and enhanced levels of nicotinamide (NAM) and adenosine diphosphate ribose (ADPr). The NAD+/NAM ratio, which was reduced in inflamed patients, served as an effective classifier for inflammation in UC. Mitochondria were also structurally altered in UC, with UC patient colonocytes displaying reduced mitochondrial density and number. Together, these findings suggest a link between mitochondrial dysfunction, inflammation, and NAD+ metabolism in UC.
    DOI:  https://doi.org/10.1371/journal.pone.0273080
  12. J Exp Med. 2022 Oct 03. pii: e20211574. [Epub ahead of print]219(10):
    TGF-β regulates the stem-like state of PD-1+ TCF-1+ virus-specific CD8 T cells during chronic infection.
    Yinghong Hu, William H Hudson, Haydn T Kissick, Christopher B Medina, Antonio P Baptista, Chaoyu Ma, Wei Liao, Ronald N Germain, Shannon J Turley, Nu Zhang, Rafi Ahmed.
      Recent studies have defined a novel population of PD-1+ TCF-1+ stem-like CD8 T cells in chronic infections and cancer. These quiescent cells reside in lymphoid tissues, are critical for maintaining the CD8 T cell response under conditions of persistent antigen, and provide the proliferative burst after PD-1 blockade. Here we examined the role of TGF-β in regulating the differentiation of virus-specific CD8 T cells during chronic LCMV infection of mice. We found that TGF-β signaling was not essential for the generation of the stem-like CD8 T cells but was critical for maintaining the stem-like state and quiescence of these cells. TGF-β regulated the unique transcriptional program of the stem-like subset, including upregulation of inhibitory receptors specifically expressed on these cells. TGF-β also promoted the terminal differentiation of exhausted CD8 T cells by suppressing the effector-associated program. Together, the absence of TGF-β signaling resulted in significantly increased accumulation of effector-like CD8 T cells. These findings have implications for immunotherapies in general and especially for T cell therapy against chronic infections and cancer.
    DOI:  https://doi.org/10.1084/jem.20211574
  13. Trends Immunol. 2022 Aug 11. pii: S1471-4906(22)00141-7. [Epub ahead of print]
    NF-κB: blending metabolism, immunity, and inflammation.
    Daria Capece, Daniela Verzella, Irene Flati, Paola Arboretto, Jessica Cornice, Guido Franzoso.
      The procurement and management of nutrients and ability to fight infections are fundamental requirements for survival. These defense responses are bioenergetically costly, requiring the immune system to balance protection against pathogens with the need to maintain metabolic homeostasis. NF-κB transcription factors are central regulators of immunity and inflammation. Over the last two decades, these factors have emerged as a pivotal node coordinating the immune and metabolic systems in physiology and the etiopathogenesis of major threats to human health, including cancer, autoimmunity, chronic inflammation, and others. In this review, we discuss recent advances in understanding how NF-κB-dependent metabolic programs control inflammation, metabolism, and immunity and how improved knowledge of them may lead to better diagnostics and therapeutics for widespread human diseases.
    DOI:  https://doi.org/10.1016/j.it.2022.07.004
  14. Nat Commun. 2022 Aug 16. 13(1): 4827
    A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues.
    Dominik Saul, Robyn Laura Kosinsky, Elizabeth J Atkinson, Madison L Doolittle, Xu Zhang, Nathan K LeBrasseur, Robert J Pignolo, Paul D Robbins, Laura J Niedernhofer, Yuji Ikeno, Diana Jurk, João F Passos, LaTonya J Hickson, Ailing Xue, David G Monroe, Tamara Tchkonia, James L Kirkland, Joshua N Farr, Sundeep Khosla.
      Although cellular senescence drives multiple age-related co-morbidities through the senescence-associated secretory phenotype, in vivo senescent cell identification remains challenging. Here, we generate a gene set (SenMayo) and validate its enrichment in bone biopsies from two aged human cohorts. We further demonstrate reductions in SenMayo in bone following genetic clearance of senescent cells in mice and in adipose tissue from humans following pharmacological senescent cell clearance. We next use SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from human and murine bone marrow/bone scRNA-seq data. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Using this senescence panel, we are able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways. SenMayo also represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.
    DOI:  https://doi.org/10.1038/s41467-022-32552-1
  15. Mol Cell. 2022 Aug 12. pii: S1097-2765(22)00703-1. [Epub ahead of print]
    Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells.
    Yahui Wang, Ethan Stancliffe, Ronald Fowle-Grider, Rencheng Wang, Cheng Wang, Michaela Schwaiger-Haber, Leah P Shriver, Gary J Patti.
      Proliferating cells exhibit a metabolic phenotype known as "aerobic glycolysis," which is characterized by an elevated rate of glucose fermentation to lactate irrespective of oxygen availability. Although several theories have been proposed, a rationalization for why proliferating cells seemingly waste glucose carbon by excreting it as lactate remains elusive. Using the NCI-60 cell lines, we determined that lactate excretion is strongly correlated with the activity of mitochondrial NADH shuttles, but not proliferation. Quantifying the fluxes of the malate-aspartate shuttle (MAS), the glycerol 3-phosphate shuttle (G3PS), and lactate dehydrogenase under various conditions demonstrated that proliferating cells primarily transform glucose to lactate when glycolysis outpaces the mitochondrial NADH shuttles. Increasing mitochondrial NADH shuttle fluxes decreased glucose fermentation but did not reduce the proliferation rate. Our results reveal that glucose fermentation, a hallmark of cancer, is a secondary consequence of MAS and G3PS saturation rather than a unique metabolic driver of cellular proliferation.
    Keywords:  NADH shuttles; aerobic glycolysis; cancer metabolism; glycerol 3-phosphate shuttle; isotope-tracer analysis; malate-aspartate shuttle; metabolic flux; metabolomics; the Warburg effect
    DOI:  https://doi.org/10.1016/j.molcel.2022.07.007
  16. Bioimpacts. 2022 ;12(4): 337-347
    CRISPRi-mediated knock-down of PRDM1/BLIMP1 programs central memory differentiation in ex vivo-expanded human T cells.
    Mohammad Azadbakht, Ali Sayadmanesh, Naghme Nazer, Amirhossein Ahmadi, Sara Hemmati, Hoda Mohammadzade, Marzieh Ebrahimi, Hossein Baharvand, Babak Khalaj, Mahmoud Reza Aghamaali, Mohsen Basiri.
      Introduction: B lymphocyte-induced maturation protein 1 (BLIMP1) encoded by the positive regulatory domain 1 gene (PRDM1), is a key regulator in T cell differentiation in mouse models. BLIMP1-deficiency results in a lower effector phenotype and a higher memory phenotype. Methods: In this study, we aimed to determine the role of transcription factor BLIMP1 in human T cell differentiation. Specifically, we investigated the role of BLIMP1 in memory differentiation and exhaustion of human T cells. We used CRISPR interference (CRISPRi) to knock-down BLIMP1 and investigated the differential expressions of T cell memory and exhaustion markers in BLIMP1-deficient T cells in comparison with BLIMP1-sufficient ex vivo expanded human T cells. Results: BLIMP1-deficiency caused an increase in central memory (CM) T cells and a decrease in effector memory (EM) T cells. There was a decrease in the amount of TIM3 exhaustion marker expression in BLIMP1-deficient T cells; however, there was an increase in PD1 exhaustion marker expression in BLIMP1-deficient T cells compared with BLIMP1-sufficient T cells. Conclusion: Our study provides the first functional evidence of the impact of BLIMP1 on the regulation of human T cell memory and exhaustion phenotype. These findings suggest that BLIMP1 may be a promising target to improve the immune response in adoptive T cell therapy settings.
    Keywords:  BLIMP1; CRISPR interference; Memory T cell; PRDM1; T cell
    DOI:  https://doi.org/10.34172/bi.2021.23522
  17. Immunometabolism (Cobham). 2022 Jul;4(3): e00003
    Glucose transport in the regulation of T-cell activation: the journey may be as important as the destination.
    Steven W Barger.
      A shift in the energy-metabolism balance from oxidative phosphorylation to glycolysis is observed in several phenomena, from oncogenesis to differentiation. And this shift is not merely an indicator of the phenotypic change-an increase in glucose delivery often drives the adaption. At first blush, it seems that any route of entry should be equivalent, as long as sufficient quantities are supplied. However, an extensive study comparing the Th17 and Th1 subtypes of T cells now suggests that similar glucose transporters may not be interchangeable. Manipulation of individual transporters, or the downstream metabolites of their substrates, may afford dampening of autoimmunity potential with some degree of precision.
    Keywords:  T cells; gene expression; glucose; glucose transporter; metabolism
    DOI:  https://doi.org/10.1097/IN9.0000000000000003
  18. J Exp Med. 2022 Oct 03. pii: e20211538. [Epub ahead of print]219(10):
    TGF-β promotes stem-like T cells via enforcing their lymphoid tissue retention.
    Chaoyu Ma, Liwen Wang, Wei Liao, Yong Liu, Shruti Mishra, Guo Li, Xin Zhang, Yuanzheng Qiu, Qianjin Lu, Nu Zhang.
      Stem-like CD8+ T cells sustain the antigen-specific CD8+ T cell response during chronic antigen exposure. However, the signals that control the maintenance and differentiation of these cells are largely unknown. Here, we demonstrated that TGF-β was essential for the optimal maintenance of these cells and inhibited their differentiation into migratory effectors during chronic viral infection. Mechanistically, stem-like CD8+ T cells carried a unique expression pattern of α4 integrins (i.e., α4β1hi and α4β7lo) controlled by TGF-β. In the absence of TGF-β signaling, greatly enhanced expression of migration-related markers, including altered expression of α4 integrins, led to enhanced egress of stem-like CD8+ T cells into circulation accompanied by further differentiation into transitional states. Blocking α4 integrin significantly promoted their lymphoid tissue retention and therefore partially rescued the defective maintenance of Tcf-1+ subset in the absence of TGF-β signaling. Thus, TGF-β promotes the maintenance and inhibits the further differentiation of stem-like T cells at least partially via enforcing their lymphoid tissue residency.
    DOI:  https://doi.org/10.1084/jem.20211538
  19. Front Integr Neurosci. 2022 ;16 929788
    A protocol for rapid construction of senescent cells.
    Xing Yu, Jing Quan, Shuai Chen, Xinyue Yang, Shuai Huang, Gang Yang, Yujing Zhang.
      Aging may be the largest factor for a variety of chronic diseases that influence survival, independence, and wellbeing. Evidence suggests that aging could be thought of as the modifiable risk factor to delay or alleviate age-related conditions as a group by regulating essential aging mechanisms. One such mechanism is cellular senescence, which is a special form of most cells that are present as permanent cell cycle arrest, apoptosis resistance, expression of anti-proliferative molecules, acquisition of pro-inflammatory, senescence-associated secretory phenotype (SASP), and others. Most cells cultured in vitro or in vivo may undergo cellular senescence after accruing a set number of cell divisions or provoked by excessive endogenous and exogenous stress or damage. Senescent cells occur throughout life and play a vital role in various physiological and pathological processes such as embryogenesis, wound healing, host immunity, and tumor suppression. In contrast to the beneficial senescent processes, the accumulation of senescent also has deleterious effects. These non-proliferating cells lead to the decrease of regenerative potential or functions of tissues, inflammation, and other aging-associated diseases because of the change of tissue microenvironment with the acquisition of SASP. While it is understood that age-related diseases occur at the cellular level from the cellular senescence, the mechanisms of cellular senescence in age-related disease progression remain largely unknown. Simplified and rapid models such as in vitro models of the cellular senescence are critically needed to deconvolute mechanisms of age-related diseases. Here, we obtained replicative senescent L02 hepatocytes by culturing the cells for 20 weeks. Then, the conditioned medium containing supernatant from replicative senescent L02 hepatocytes was used to induce cellular senescence, which could rapidly induce hepatocytes into senescence. In addition, different methods were used to validate senescence, including senescence-associated β-galactosidase (SA-β-gal), the rate of DNA synthesis using 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, and senescence-related proteins. At last, we provide example results and discuss further applications of the protocol.
    Keywords:  SASP; aging; biomarker; cellular senescence; senescent cell models
    DOI:  https://doi.org/10.3389/fnint.2022.929788
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