bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–05–28
sixteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Pyruvate dehydrogenase complex integrates the metabolome and epigenome in CD8+ memory T cell differentiation in vitro.
  2. Correction: Naive T cells inhibit the outgrowth of intractable antigen-activated memory T cells: implications for T-cell immunotherapy.
  3. Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity.
  4. CD69 imposes tumor-specific CD8+ T-cell fate in tumor-draining lymph nodes.
  5. T cells in pancreatic cancer stroma: Tryptophan metabolism plays an important role in immunoregulation.
  6. Mitochondrial dynamics and cristae shape changes during metabolic reprogramming.
  7. Calcineurin inhibitor inhibits tolerance induction by suppressing terminal exhaustion of donor T cells after allo-HCT.
  8. ROS-Induced Mitochondrial Dysfunction in CD4 T Cells from ART-Controlled People Living with HIV.
  9. Transcriptional and metabolic programs promote the expansion of follicular helper T cells in lupus-prone mice.
  10. Glucose Transporter Glut1-Dependent Metabolic Reprogramming Regulates Lipopolysaccharide-Induced Inflammation in RAW264.7 Macrophages.
  11. Targeting Cancer Metabolism to Improve Outcomes with Immune Checkpoint Inhibitors.
  12. Mitochondrial Dysfunction: At the Nexus between Alcohol-Associated Immunometabolic Dysregulation and Tissue Injury.
  13. CXCR4 to improve both T cell homing and function.
  14. Protocol to evaluate the impact of murine MCT1-deficient CD8+ T cells on adipogenesis.
  15. A mitochondrial origin for inherited diabetes mellitus.
  16. Get me out of here: Sphingosine 1-phosphate signaling and T cell exit from tissues during an immune response.
  1. Res Sq. 2023 May 10. pii: rs.3.rs-2838359. [Epub ahead of print]
    Pyruvate dehydrogenase complex integrates the metabolome and epigenome in CD8+ memory T cell differentiation in vitro.
    Tatiana Tarasenko, Payal Banerjee, Julio Gomez-Rodriguez, Derek Gildea, Suiyuan Zhang, Tyra Wolfsberg, Lisa Jenkins, Nisc Comparative Sequencing Program, Peter McGuire.
      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. 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. 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. TPdh -/- T cells became dependent upon substrate level phosphorylation via glycolysis, secondary to depressed OXPHOS. Due to the block of PDC activity, histone acetylation was also reduced, including H3K27, a critical site for CD8 + T M differentiation. Transcriptional and functional profiling revealed abnormal CD8 + T M differentiation in vitro. Collectively, our data indicate that PDC integrates the metabolome and epigenome in CD8 + 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-2838359/v1
  2. J Immunother Cancer. 2023 May;pii: e006267corr1. [Epub ahead of print]11(5):
    Correction: Naive T cells inhibit the outgrowth of intractable antigen-activated memory T cells: implications for T-cell immunotherapy.
      
    DOI:  https://doi.org/10.1136/jitc-2022-006267corr1
  3. Cell Metab. 2023 May 17. pii: S1550-4131(23)00178-X. [Epub ahead of print]
    Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity.
    Benjamin J Jenkins, Julianna Blagih, Fernando M Ponce-Garcia, Mary Canavan, Nancy Gudgeon, Simon Eastham, David Hill, Megan M Hanlon, Eric H Ma, Emma L Bishop, April Rees, James G Cronin, Elizabeth C Jury, Sarah K Dimeloe, Douglas J Veale, Catherine A Thornton, Karen H Vousden, David K Finlay, Ursula Fearon, Gareth W Jones, Linda V Sinclair, Emma E Vincent, Nicholas Jones.
      Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity.
    Keywords:  CD4 T cell; T cell; autoimmunity; canagliflozin; gliflozins; human; immunometabolism
    DOI:  https://doi.org/10.1016/j.cmet.2023.05.001
  4. Cancer Immunol Res. 2023 May 22. pii: CIR-22-0406. [Epub ahead of print]
    CD69 imposes tumor-specific CD8+ T-cell fate in tumor-draining lymph nodes.
    Ryo Koyama-Nasu, Motoko Y Kimura, Masahiro Kiuchi, Ami Aoki, Yangsong Wang, Yukiyoshi Mita, Ichita Hasegawa, Yukihiro Endo, Atsushi Onodera, Kiyoshi Hirahara, Shinichiro Motohashi, Toshinori Nakayama.
      Tumor-specific CD8+ T cells play a pivotal role in anti-tumor immunity and are a key target of immunotherapeutic approaches. Intratumoral CD8+ T cells are heterogeneous; Tcf1+ stem-like CD8+ T cells give rise to their cytotoxic progeny - Tim-3+ terminally differentiated CD8+ T cells. However, where and how this differentiation process occurs has not been elucidated. We herein show that terminally differentiated CD8+ T cells can be generated within tumor-draining lymph nodes (TDLNs) and that CD69 expression on tumor-specific CD8+ T cells controls its differentiation process through regulating the expression of the transcription factor TOX. In TDLNs, CD69 deficiency diminished TOX expression in tumor-specific CD8+ T cells, and consequently promoted generation of functional terminally differentiated CD8+ T cells. Anti-CD69 administration promoted the generation of terminally differentiated CD8+ T cells, and the combined use of anti-CD69 and anti-PD-1 showed an efficient anti-tumor effect. Thus, CD69 is an attractive target for cancer immunotherapy that synergizes with immune checkpoint blockade.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-22-0406
  5. World J Gastroenterol. 2023 May 07. 29(17): 2701-2703
    T cells in pancreatic cancer stroma: Tryptophan metabolism plays an important role in immunoregulation.
    Ting Yang, Qiao-Qi Li, Yong-Mei Liu, Biao Yang.
      Several studies have shown that the immune system is highly regulated by tryptophan metabolism, which serves as an immunomodulatory factor. The indoleamine 2,3-dioxygenase 1 (IDO1), as an intracellular enzyme that participates in metabolism of the essential amino acid tryptophan in the kynurenine pathway, is an independent prognostic marker for pancreatic cancer (PC). First, overexpression of IDO1 inhibits the maturation of dendritic cells and T-cell proliferation in the liver and spleen. Second, the high expression of kynurenine induces and activates the aryl hydrocarbon receptor, resulting in upregulated programmed cell death protein 1 expression. Third, the induction of IDO1 can lead to loss of the T helper 17 cell/regulatory T cell balance, mediated by the proximal tryptophan catabolite from IDO metabolism. In our study, we found that overexpression of IDO1 upregulated CD8+ T cells and reduced natural killer T cells in pancreatic carcinoma in mice. Hence, it may be essential to pay more attention to tryptophan metabolism in patients, especially those who are tolerant to immunotherapy for PC.
    Keywords:  Immunosuppression; Pancreatic cancer stroma; T cell; Tryptophan metabolism; Xxx
    DOI:  https://doi.org/10.3748/wjg.v29.i17.2701
  6. Antioxid Redox Signal. 2023 May 22.
    Mitochondrial dynamics and cristae shape changes during metabolic reprogramming.
    Ippei Kawano, Bazila Bazila, Petr Jezek, Andrea Dlasková.
       SIGNIFICANCE: The architecture of the mitochondrial network and cristae critically impact cell differentiation and identity. Cells undergoing metabolic reprogramming to aerobic glycolysis (Warburg effect), such as immune cells, stem cells, and cancer cells, go through controlled modifications in mitochondrial architecture, which is critical for achieving the resulting cellular phenotype.
    RECENT ADVANCES: Recent studies in immunometabolism have shown that the manipulation of mitochondrial network dynamics and cristae shape directly affects T cell phenotype and macrophage polarization through altering energy metabolism. Similar manipulations also alter the specific metabolic phenotypes that accompany somatic reprogramming, stem cell differentiation, and cancer cells. The modulation of OXPHOS activity, accompanied by changes in metabolite signaling, ROS generation, and ATP levels is the shared underlying mechanism.
    CRITICAL ISSUES: The plasticity of mitochondrial architecture is particularly vital for metabolic reprogramming. Consequently, failure to adapt the appropriate mitochondrial morphology often compromises the differentiation and identity of the cell. Immune, stem, and tumor cells exhibit striking similarities in their coordination of mitochondrial morphology with metabolic pathways. However, although many general unifying principles can be observed, their validity is not absolute, and the mechanistic links thus need to be further explored.
    FUTURE DIRECTIONS: Better knowledge of the molecular mechanisms involved and their relationships to both mitochondrial network and cristae morphology will not only further deepen our understanding of energy metabolism but may also contribute to improved therapeutic manipulation of cell viability, differentiation, proliferation, and identity in many different cell types.
    DOI:  https://doi.org/10.1089/ars.2023.0268
  7. Blood. 2023 May 22. pii: blood.2023019875. [Epub ahead of print]
    Calcineurin inhibitor inhibits tolerance induction by suppressing terminal exhaustion of donor T cells after allo-HCT.
    Hajime Senjo, Shinpei Harada, Shimpei I Kubota, Yuki Tanaka, Takahiro Tateno, Zixuan Zhang, Satomi Okada, Xuanzhong Chen, Ryo Kikuchi, Naoki Miyashita, Masahiro Onozawa, Hideki Goto, Tomoyuki Endo, Yuta Hasegawa, Hiroyuki Ohigashi, Takahide Ara, Yoshinori Hasegawa, Masaaki Murakami, Takanori Teshima, Daigo Hashimoto.
      Calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis is standard in allogeneic hematopoietic stem cell transplantation (HCT) but fails to induce long-term tolerance without chronic GVHD in a considerable number of patients. In this study, we addressed this long-standing question in mouse models of HCT. After HCT, alloreactive donor T cells rapidly differentiated into PD-1+ TIGIT+ terminally exhausted T cells (terminal-Tex). GVHD prophylaxis with cyclosporine (CSP) suppressed donor T-cell expression of TOX, a master regulator to promote differentiation of transitory exhausted T cells (transitory-Tex), expressing both inhibitory receptors and effector molecules, into terminal-Tex, and inhibited tolerance induction. Adoptive transfer of transitory-Tex, but not terminal-Tex, into secondary recipients developed chronic GVHD. Transitory-Tex maintained alloreactivity and thus PD-1 blockade restored graft-versus-leukemia (GVL) activity of transitory-Tex, not terminal-Tex. In conclusion, CSP inhibits tolerance induction by suppressing the terminal exhaustion of donor T cells, while maintaining GVL effects to suppress leukemia relapse.
    DOI:  https://doi.org/10.1182/blood.2023019875
  8. Viruses. 2023 Apr 26. pii: 1061. [Epub ahead of print]15(5):
    ROS-Induced Mitochondrial Dysfunction in CD4 T Cells from ART-Controlled People Living with HIV.
    Madison Schank, Juan Zhao, Ling Wang, Lam Ngoc Thao Nguyen, Yi Zhang, Xiao Y Wu, Jinyu Zhang, Yong Jiang, Shunbin Ning, Mohamed El Gazzar, Jonathan P Moorman, Zhi Q Yao.
      We have previously demonstrated mitochondrial dysfunction in aging CD4 T cells from antiretroviral therapy (ART)-controlled people living with HIV (PLWH). However, the underlying mechanisms by which CD4 T cells develop mitochondrial dysfunction in PLWH remain unclear. In this study, we sought to elucidate the mechanism(s) of CD4 T cell mitochondrial compromise in ART-controlled PLWH. We first assessed the levels of reactive oxygen species (ROS), and we observed significantly increased cellular and mitochondrial ROS levels in CD4 T cells from PLWH compared to healthy subjects (HS). Furthermore, we observed a significant reduction in the levels of proteins responsible for antioxidant defense (superoxide dismutase 1, SOD1) and ROS-mediated DNA damage repair (apurinic/apyrimidinic endonuclease 1, APE1) in CD4 T cells from PLWH. Importantly, CRISPR/Cas9-mediated knockdown of SOD1 or APE1 in CD4 T cells from HS confirmed their roles in maintaining normal mitochondrial respiration via a p53-mediated pathway. Reconstitution of SOD1 or APE1 in CD4 T cells from PLWH successfully rescued mitochondrial function as evidenced by Seahorse analysis. These results indicate that ROS induces mitochondrial dysfunction, leading to premature T cell aging via dysregulation of SOD1 and APE1 during latent HIV infection.
    Keywords:  PLWH; T cell aging; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.3390/v15051061
  9. iScience. 2023 May 19. 26(5): 106774
    Transcriptional and metabolic programs promote the expansion of follicular helper T cells in lupus-prone mice.
    Minghao Gong, Seung-Chul Choi, Yuk Pheel Park, Xueyang Zou, Ahmed S Elshikha, Valerie A Gerriets, Jeffrey C Rathmell, Mansour Mohamazadeh, Laurence Morel.
      The expansion of follicular helper T (Tfh) cells, which is tightly associated with the development of lupus, is reversed by the inhibition of either glycolysis or glutaminolysis in mice. Here we analyzed the gene expression and metabolome of Tfh cells and naive CD4+ T (Tn) cells in the B6.Sle1.Sle2.Sle3 (triple congenic, TC) mouse model of lupus and its congenic B6 control. Lupus genetic susceptibility in TC mice drives a gene expression signature starting in Tn cells and expanding in Tfh cells with enhanced signaling and effector programs. Metabolically, TC Tn and Tfh cells showed multiple defective mitochondrial functions. TC Tfh cells also showed specific anabolic programs including enhanced glutamate metabolism, malate-aspartate shuttle, and ammonia recycling, as well as altered dynamics of amino acid content and their transporters. Thus, our study has revealed specific metabolic programs that can be targeted to specifically limit the expansion of pathogenic Tfh cells in lupus.
    Keywords:  Cell biology; Immunology; Metabolomics; Physiology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2023.106774
  10. Biomolecules. 2023 Apr 29. pii: 770. [Epub ahead of print]13(5):
    Glucose Transporter Glut1-Dependent Metabolic Reprogramming Regulates Lipopolysaccharide-Induced Inflammation in RAW264.7 Macrophages.
    Alex Cornwell, Hubert Ziółkowski, Alireza Badiei.
      This study investigated the critical role of Glut1-mediated glucose metabolism in the inflammatory response of macrophages, which are energy-intensive cells within the innate immune system. Inflammation leads to increased Glut1 expression, ensuring sufficient glucose uptake to support macrophage functions. We demonstrated that using siRNA to knock down Glut1 reduces the expression of various pro-inflammatory cytokines and markers, such as IL-6, iNOS, MHC II/CD40, reactive oxygen species, and the hydrogen sulfide (H2S)-producing enzyme cystathionine γ-lyase (CSE). Glut1 activates a pro-inflammatory profile through a nuclear factor (NF)-κB, while silencing Glut1 can prevent lipopolysaccharide (LPS)-induced IκB degradation, blocking NF-κB activation. Glut1's role in autophagy, an essential process for macrophage functions such as antigen presentation, phagocytosis, and cytokine secretion, was also measured. The findings show that LPS stimulation decreases autophagosome formation, but Glut1 knockdown reverses this effect, increasing autophagy beyond control levels. The study highlights Glut1's importance in macrophage immune responses and its regulation of apoptosis during LPS stimulation. Knocking down Glut1 negatively impacts cell viability and mitochondrial intrinsic pathway signaling. These findings collectively suggest that targeting macrophage glucose metabolism through Glut1 could potentially serve as a target for controlling inflammation.
    Keywords:  Glut 1; autophagy; hydrogen sulfide; inflammation; macrophage
    DOI:  https://doi.org/10.3390/biom13050770
  11. J Immunother Precis Oncol. 2023 May;6(2): 91-102
    Targeting Cancer Metabolism to Improve Outcomes with Immune Checkpoint Inhibitors.
    Zainab Fatima, Abdulrahman Abonofal, Bettzy Stephen.
      Immune checkpoint inhibitors have revolutionized the treatment paradigm of several cancers. However, not all patients respond to treatment. Tumor cells reprogram metabolic pathways to facilitate growth and proliferation. This shift in metabolic pathways creates fierce competition with immune cells for nutrients in the tumor microenvironment and generates by-products harmful for immune cell differentiation and growth. In this review, we discuss these metabolic alterations and the current therapeutic strategies to mitigate these alterations to metabolic pathways that can be used in combination with checkpoint blockade to offer a new path forward in cancer management.
    Keywords:  adenosine pathway; amino acid metabolism; glucose metabolism; immune checkpoint inhibitors; lipid metabolism
    DOI:  https://doi.org/10.36401/JIPO-22-27
  12. Int J Mol Sci. 2023 May 12. pii: 8650. [Epub ahead of print]24(10):
    Mitochondrial Dysfunction: At the Nexus between Alcohol-Associated Immunometabolic Dysregulation and Tissue Injury.
    Robert W Siggins, Patrick M McTernan, Liz Simon, Flavia M Souza-Smith, Patricia E Molina.
      Alcohol misuse, directly or indirectly as a result of its metabolism, negatively impacts most tissues, including four with critical roles in energy metabolism regulation: the liver, pancreas, adipose, and skeletal muscle. Mitochondria have long been studied for their biosynthetic roles, such as ATP synthesis and initiation of apoptosis. However, current research has provided evidence that mitochondria participate in myriad cellular processes, including immune activation, nutrient sensing in pancreatic β-cells, and skeletal muscle stem and progenitor cell differentiation. The literature indicates that alcohol impairs mitochondrial respiratory capacity, promoting reactive oxygen species (ROS) generation and disrupting mitochondrial dynamics, leading to dysfunctional mitochondria accumulation. As discussed in this review, mitochondrial dyshomeostasis emerges at a nexus between alcohol-disrupted cellular energy metabolism and tissue injury. Here, we highlight this link and focus on alcohol-mediated disruption of immunometabolism, which refers to two distinct, yet interrelated processes. Extrinsic immunometabolism involves processes whereby immune cells and their products influence cellular and/or tissue metabolism. Intrinsic immunometabolism describes immune cell fuel utilization and bioenergetics that affect intracellular processes. Alcohol-induced mitochondrial dysregulation negatively impacts immunometabolism in immune cells, contributing to tissue injury. This review will present the current state of literature, describing alcohol-mediated metabolic and immunometabolic dysregulation from a mitochondrial perspective.
    Keywords:  adaptive immunity; adipose tissue; alcohol; innate immunity; liver; mitochondria; pancreas; skeletal muscle immunometabolism
    DOI:  https://doi.org/10.3390/ijms24108650
  13. Blood. 2023 May 25. 141(21): 2546-2547
    CXCR4 to improve both T cell homing and function.
    Miriam Y Kim.
      
    DOI:  https://doi.org/10.1182/blood.2023020050
  14. STAR Protoc. 2023 May 19. pii: S2666-1667(23)00268-X. [Epub ahead of print]4(2): 102301
    Protocol to evaluate the impact of murine MCT1-deficient CD8+ T cells on adipogenesis.
    Chiara Macchi, Annalisa Moregola, Giuseppe Danilo Norata, Massimiliano Ruscica.
      The infiltration of activated T cells, such as CD8+ effector, in metabolic tissues plays a crucial role for the initiation and propagation of obesity-induced inflammation. Given the pivotal role of lactate transporter monocarboxylate transporter 1 (MCT1) in immune cell activation, we present a protocol for the isolation and activation of CD8+ T lymphocytes selectively lacking MCT1. We describe steps for the induction of adipocyte differentiation, CD8+ T isolation and activation, and adipocyte-CD8+ T cell co-culture. We then detail qPCR analysis on differentiated adipocytes. For complete details on the use and execution of this protocol, please refer to Macchi et al.1.
    Keywords:  Cell Biology; Cell culture; Cell isolation; Flow Cytometry/Mass Cytometry; Metabolism; Model Organisms; Molecular Biology
    DOI:  https://doi.org/10.1016/j.xpro.2023.102301
  15. Nat Rev Endocrinol. 2023 May 26.
    A mitochondrial origin for inherited diabetes mellitus.
    Brandon J Berry.
      
    DOI:  https://doi.org/10.1038/s41574-023-00856-x
  16. Immunol Rev. 2023 May 22.
    Get me out of here: Sphingosine 1-phosphate signaling and T cell exit from tissues during an immune response.
    Victoria M Hallisey, Susan R Schwab.
      During an immune response, the duration of T cell residence in lymphoid and non-lymphoid tissues likely affects T cell activation, differentiation, and memory development. The factors that govern T cell transit through inflamed tissues remain incompletely understood, but one important determinant of T cell exit from tissues is sphingosine 1-phosphate (S1P) signaling. In homeostasis, S1P levels are high in blood and lymph compared to lymphoid organs, and lymphocytes follow S1P gradients out of tissues into circulation using varying combinations of five G-protein coupled S1P receptors. During an immune response, both the shape of S1P gradients and the expression of S1P receptors are dynamically regulated. Here we review what is known, and key questions that remain unanswered, about how S1P signaling is regulated in inflammation and in turn how S1P shapes immune responses.
    Keywords:  T cells; cell trafficking; chemokines; lipid mediators; lymph nodes
    DOI:  https://doi.org/10.1111/imr.13219
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