bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–04–28
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Extracellular domains of CARs reprogramme T cell metabolism without antigen stimulation.
  2. Gfi1 controls the formation of effector CD8 T cells during chronic infection and cancer.
  3. Highlight of 2023: Unraveling the complexity of T cell aging - insights from recent advances.
  4. PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells.
  5. Sphingolipid biosynthesis is essential for metabolic rewiring during TH17 cell differentiation.
  6. The potential role of CMC1 as an immunometabolic checkpoint in T cell immunity.
  7. Reprogramming T cells as an emerging treatment to slow human age-related decline in health.
  8. Microbiota-derived inosine programs protective CD8+ T cell responses against influenza in newborns.
  9. PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.
  10. Metabolite accumulation from oral NMN supplementation drives aging-specific kidney inflammation.
  11. Publisher Correction: FOXO1 is a master regulator of memory programming in CAR T cells.
  12. Zinc Ionophore Pyrithione Mimics CD28 Costimulatory Signal in CD3 Activated T Cells.
  13. Deciphering the importance of culture pH on CD22 CAR T-cells characteristics.
  1. Nat Metab. 2024 Apr 24.
    Extracellular domains of CARs reprogramme T cell metabolism without antigen stimulation.
    Aliya Lakhani, Ximin Chen, Laurence C Chen, Mihe Hong, Mobina Khericha, Yu Chen, Yvonne Y Chen, Junyoung O Park.
      Metabolism is an indispensable part of T cell proliferation, activation and exhaustion, yet the metabolism of chimeric antigen receptor (CAR)-T cells remains incompletely understood. CARs are composed of extracellular domains-often single-chain variable fragments (scFvs)-that determine ligand specificity and intracellular domains that trigger signalling following antigen binding. Here, we show that CARs differing only in the scFv variously reprogramme T cell metabolism. Even without exposure to antigens, some CARs increase proliferation and nutrient uptake in T cells. Using stable isotope tracers and mass spectrometry, we observed basal metabolic fluxes through glycolysis doubling and amino acid uptake overtaking anaplerosis in CAR-T cells harbouring a rituximab scFv, unlike other similar anti-CD20 scFvs. Disparate rituximab and 14G2a-based anti-GD2 CAR-T cells are similarly hypermetabolic and channel excess nutrients to nitrogen overflow metabolism. Modest overflow metabolism of CAR-T cells and metabolic compatibility between cancer cells and CAR-T cells are identified as features of efficacious CAR-T cell therapy.
    DOI:  https://doi.org/10.1038/s42255-024-01034-7
  2. bioRxiv. 2024 Apr 21. pii: 2024.04.18.579535. [Epub ahead of print]
    Gfi1 controls the formation of effector CD8 T cells during chronic infection and cancer.
    Oluwagbemiga A Ojo, Hongxing Shen, Jennifer T Ingram, James A Bonner, Robert S Welner, Georges Lacaud, Allan J Zajac, Lewis Z Shi.
      During chronic infections and tumor progression, CD8 T cells gradually lose their effector functions and become exhausted. These exhausted CD8 T cells are heterogeneous and comprised of different subsets, including self-renewing progenitors that give rise to Ly108 - CX3CR1 + effector-like cells. Generation of these effector-like cells is essential for the control of chronic infections and tumors, albeit limited. However, the precise cues and mechanisms directing the formation and maintenance of exhausted effector-like are incompletely understood. Using genetic mouse models challenged with LCMV Clone 13 or syngeneic tumors, we show that the expression of a transcriptional repressor, growth factor independent 1 (Gfi1) is dynamically regulated in exhausted CD8 T cells, which in turn regulates the formation of exhausted effector-like cells. Gfi1 deletion in T cells dysregulates the chromatin accessibility and transcriptomic programs associated with the differentiation of LCMV Clone 13-specific CD8 T cell exhaustion, preventing the formation of effector-like and terminally exhausted cells while maintaining progenitors and a newly identified Ly108 + CX3CR1 + state. These Ly108 + CX3CR1 + cells have a distinct chromatin profile and may represent an alternative target for therapeutic interventions to combat chronic infections and cancer. In sum, we show that Gfi1 is a critical regulator of the formation of exhausted effector-like cells.
    DOI:  https://doi.org/10.1101/2024.04.18.579535
  3. Immunol Cell Biol. 2024 Apr 22.
    Highlight of 2023: Unraveling the complexity of T cell aging - insights from recent advances.
    Jing Guo, Zhonghui Xue, Lie Wang.
      Unraveling the complexities of T cell aging is essential for developing targeted interventions to enhance immune function in the elderly. This article for the Highlights of 2023 Series integrates recent findings published in 2023, offering a panoramic view of the current understanding of T cell aging and its implications.
    Keywords:  CD4+ T cells; CD8+ T cells; Immunosenescence; T cell aging
    DOI:  https://doi.org/10.1111/imcb.12755
  4. Nature. 2024 Apr 24.
    PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells.
    Sebastian B Lacher, Janina Dörr, Gustavo P de Almeida, Julian Hönninger, Felix Bayerl, Anna Hirschberger, Anna-Marie Pedde, Philippa Meiser, Lukas Ramsauer, Thomas J Rudolph, Nadine Spranger, Matteo Morotti, Alizee J Grimm, Sebastian Jarosch, Arman Oner, Lisa Gregor, Stefanie Lesch, Stefanos Michaelides, Luisa Fertig, Daria Briukhovetska, Lina Majed, Sophia Stock, Dirk H Busch, Veit R Buchholz, Percy A Knolle, Dietmar Zehn, Denarda Dangaj Laniti, Sebastian Kobold, Jan P Böttcher.
      Cancer-specific TCF1+ stem-like CD8+ T cells can drive protective anticancer immunity through expansion and effector cell differentiation1-4; however, this response is dysfunctional in tumours. Current cancer immunotherapies2,5-9 can promote anticancer responses through TCF1+ stem-like CD8+ T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1+CD8+ T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE2) restricts the proliferative expansion and effector differentiation of TCF1+CD8+ T cells within tumours, which promotes cancer immune escape. PGE2 does not affect the priming of TCF1+CD8+ T cells in draining lymph nodes. PGE2 acts through EP2 and EP4 (EP2/EP4) receptor signalling in CD8+ T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1+ tumour-infiltrating CD8+ T lymphocytes (TILs). Ablation of EP2/EP4 signalling in cancer-specific CD8+ T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE2-mediated inhibition of TCF1+ TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1+ TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE2-EP2/EP4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.
    DOI:  https://doi.org/10.1038/s41586-024-07254-x
  5. Sci Adv. 2024 Apr 26. 10(17): eadk1045
    Sphingolipid biosynthesis is essential for metabolic rewiring during TH17 cell differentiation.
    Thiruvaimozhi Abimannan, Velayoudame Parthibane, Si-Hung Le, Nagampalli Vijaykrishna, Stephen D Fox, Baktiar Karim, Govind Kunduri, Daniel Blankenberg, Thorkell Andresson, Takeshi Bamba, Usha Acharya, Jairaj K Acharya.
      T helper 17 (TH17) cells are implicated in autoimmune diseases, and several metabolic processes are shown to be important for their development and function. In this study, we report an essential role for sphingolipids synthesized through the de novo pathway in TH17 cell development. Deficiency of SPTLC1, a major subunit of serine palmitoyl transferase enzyme complex that catalyzes the first and rate-limiting step of de novo sphingolipid synthesis, impaired glycolysis in differentiating TH17 cells by increasing intracellular reactive oxygen species (ROS) through enhancement of nicotinamide adenine dinucleotide phosphate oxidase 2 activity. Increased ROS leads to impaired activation of mammalian target of rapamycin C1 and reduced expression of hypoxia-inducible factor 1-alpha and c-Myc-induced glycolytic genes. SPTLCI deficiency protected mice from developing experimental autoimmune encephalomyelitis and experimental T cell transfer colitis. Our results thus show a critical role for de novo sphingolipid biosynthetic pathway in shaping adaptive immune responses with implications in autoimmune diseases.
    DOI:  https://doi.org/10.1126/sciadv.adk1045
  6. Oncoimmunology. 2024 ;13(1): 2344905
    The potential role of CMC1 as an immunometabolic checkpoint in T cell immunity.
    Yuwen Chen, Jie Gao, Mingyue Ma, Ke Wang, Fangming Liu, Feiyu Yang, Xin Zou, Zhouli Cheng, Duojiao Wu.
      T cell immunity is critical for human defensive immune response. Exploring the key molecules during the process provides new targets for T cell-based immunotherapies. CMC1 is a mitochondrial electron transport chain (ETC) complex IV chaperon protein. By establishing in-vitro cell culture system and Cmc1 gene knock out mice, we evaluated the role of CMC1 in T cell activation and differentiation. The B16-OVA tumor model was used to test the possibility of targeting CMC1 for improving T cell anti-tumor immunity. We identified CMC1 as a positive regulator in CD8+T cells activation and terminal differentiation. Meanwhile, we found that CMC1 increasingly expressed in exhausted T (Tex) cells. Genetic lost of Cmc1 inhibits the development of CD8+T cell exhaustion in mice. Instead, deletion of Cmc1 in T cells prompts cells to differentiate into metabolically and functionally quiescent cells with increased memory-like features and tolerance to cell death upon repetitive or prolonged T cell receptor (TCR) stimulation. Further, the in-vitro mechanistic study revealed that environmental lactate enhances CMC1 expression by inducing USP7, mediated stabilization and de-ubiquitination of CMC1 protein, in which a mechanism we propose here that the lactate-enriched tumor microenvironment (TME) drives CD8+TILs dysfunction through CMC1 regulatory effects on T cells. Taken together, our study unraveled the novel role of CMC1 as a T cell regulator and its possibility to be utilized for anti-tumor immunotherapy.
    Keywords:  CMC1; T cell; USP7; lactate; tumor microenvironment
    DOI:  https://doi.org/10.1080/2162402X.2024.2344905
  7. Front Med Technol. 2024 ;6 1384648
    Reprogramming T cells as an emerging treatment to slow human age-related decline in health.
    Philip V Peplow.
      
    Keywords:  age-related decline; health; human; reprogramming T cells; treatment
    DOI:  https://doi.org/10.3389/fmedt.2024.1384648
  8. bioRxiv. 2024 Apr 13. pii: 2024.04.09.588427. [Epub ahead of print]
    Microbiota-derived inosine programs protective CD8+ T cell responses against influenza in newborns.
    Joseph Stevens, Erica Culberson, Jeremy Kinder, Alicia Ramiriqui, Jerilyn Gray, Madeline Bonfield, Tzu-Yu Shao, Faris Al Gharabieh, Laura Peterson, Shelby Steinmeyer, William Zacharias, Gloria Pryhuber, Oindrila Paul, Shaon Sengupta, Theresa Alenghat, Sing Sing Way, Hitesh Deshmukh.
      The immunological defects causing susceptibility to severe viral respiratory infections due to early-life dysbiosis remain ill-defined. Here, we show that influenza virus susceptibility in dysbiotic infant mice is caused by CD8+ T cell hyporesponsiveness and diminished persistence as tissue-resident memory cells. We describe a previously unknown role for nuclear factor interleukin 3 (NFIL3) in repression of memory differentiation of CD8+ T cells in dysbiotic mice involving epigenetic regulation of T cell factor 1 (TCF 1) expression. Pulmonary CD8+ T cells from dysbiotic human infants share these transcriptional signatures and functional phenotypes. Mechanistically, intestinal inosine was reduced in dysbiotic human infants and newborn mice, and inosine replacement reversed epigenetic dysregulation of Tcf7 and increased memory differentiation and responsiveness of pulmonary CD8+ T cells. Our data unveils new developmental layers controlling immune cell activation and identifies microbial metabolites that may be used therapeutically in the future to protect at-risk newborns.
    DOI:  https://doi.org/10.1101/2024.04.09.588427
  9. Nature. 2024 Apr 24.
    PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.
    Matteo Morotti, Alizee J Grimm, Helen Carrasco Hope, Marion Arnaud, Mathieu Desbuisson, Nicolas Rayroux, David Barras, Maria Masid, Baptiste Murgues, Bovannak S Chap, Marco Ongaro, Ioanna A Rota, Catherine Ronet, Aspram Minasyan, Johanna Chiffelle, Sebastian B Lacher, Sara Bobisse, Clément Murgues, Eleonora Ghisoni, Khaoula Ouchen, Ribal Bou Mjahed, Fabrizio Benedetti, Naoill Abdellaoui, Riccardo Turrini, Philippe O Gannon, Khalil Zaman, Patrice Mathevet, Loic Lelievre, Isaac Crespo, Marcus Conrad, Gregory Verdeil, Lana E Kandalaft, Julien Dagher, Jesus Corria-Osorio, Marie-Agnes Doucey, Ping-Chih Ho, Alexandre Harari, Nicola Vannini, Jan P Böttcher, Denarda Dangaj Laniti, George Coukos.
      Expansion of antigen-experienced CD8+ T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer1. Interleukin-2 (IL-2) acts as a key regulator of CD8+ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability2,3. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE2), a known negative regulator of immune response in the tumour microenvironment4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8+ TILs via the PGE2 receptors EP2 and EP4. Mechanistically, PGE2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγc chain, resulting in defective assembly of IL-2Rβ-IL2Rγc membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE2 signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.
    DOI:  https://doi.org/10.1038/s41586-024-07352-w
  10. bioRxiv. 2024 Apr 13. pii: 2024.04.09.588624. [Epub ahead of print]
    Metabolite accumulation from oral NMN supplementation drives aging-specific kidney inflammation.
    Tara A Saleh, Jeremy Whitson, Phoebe Keiser, Praveena Prasad, Brenita C Jenkins, Tori Sodeinde, Carolyn N Mann, Peter S Rabinovitch, Melanie R McReynolds, Mariya T Sweetwyne.
      The mitochondrial-rich renal tubule cells are key regulators of blood homeostasis via excretion and reabsorption of metabolic waste. With age, tubules are subject to increasing mitochondrial dysfunction and declining nicotinamide adenine dinucleotide (NAD+) levels, both hampering ATP production efficiency. We tested two mitochondrial interventions in young (6-mo) and aged (26-mo) adult male mice: elamipretide (ELAM), a tetrapeptide in clinical trials that improves mitochondrial structure and function, and nicotinamide mononucleotide (NMN), an NAD+ intermediate and commercially available oral supplement. Kidneys were analyzed from young and aged mice after eight weeks of treatment with ELAM (3 mg/kg/day), NMN (300 mg/kg/day), or from aged mice treated with the two interventions combined (ELAM+NMN). We hypothesized that combining pharmacologic treatments to ameliorate mitochondrial dysfunction and boost NAD+ levels, would more effectively reduce kidney aging than either intervention alone. Unexpectedly, in aged kidneys, NMN increased expression of genetic markers of inflammation (IL-1β and Ccl2) and tubule injury (Kim-1). Metabolomics of endpoint sera showed that NMN-treated aged mice had higher circulating levels of uremic toxins than either aged controls or young NMN-treated mice. ELAM+NMN-treated aged mice accumulated uremic toxins like NMN-only aged mice, but reduced IL-1β and Ccl2 kidney mRNA. This suggests that pre-existing mitochondrial dysfunction in aged kidney underlies susceptibility to inflammatory signaling with NMN supplementation in aged, but not young, mice. These findings demonstrate age and tissue dependent effects on downstream metabolic accumulation from NMN and highlight the need for targeted analysis of aged kidneys to assess the safety of anti-aging supplements in older populations.
    Keywords:  elamipretide; inflammation; kidney; metabolites; nicotinamide mononucleotide
    DOI:  https://doi.org/10.1101/2024.04.09.588624
  11. Nature. 2024 Apr 23.
    Publisher Correction: FOXO1 is a master regulator of memory programming in CAR T cells.
    Alexander E Doan, Katherine P Mueller, Andy Y Chen, Geoffrey T Rouin, Yingshi Chen, Bence Daniel, John Lattin, Martina Markovska, Brett Mozarsky, Jose Arias-Umana, Robert Hapke, In-Young Jung, Alice Wang, Peng Xu, Dorota Klysz, Gabrielle Zuern, Malek Bashti, Patrick J Quinn, Zhuang Miao, Katalin Sandor, Wenxi Zhang, Gregory M Chen, Faith Ryu, Meghan Logun, Junior Hall, Kai Tan, Stephan A Grupp, Susan E McClory, Caleb A Lareau, Joseph A Fraietta, Elena Sotillo, Ansuman T Satpathy, Crystal L Mackall, Evan W Weber.
      
    DOI:  https://doi.org/10.1038/s41586-024-07450-9
  12. Int J Mol Sci. 2024 Apr 12. pii: 4302. [Epub ahead of print]25(8):
    Zinc Ionophore Pyrithione Mimics CD28 Costimulatory Signal in CD3 Activated T Cells.
    Jana Jakobs, Lothar Rink.
      Zinc is an essential trace element that plays a crucial role in T cell immunity. During T cell activation, zinc is not only structurally important, but zinc signals can also act as a second messenger. This research investigates zinc signals in T cell activation and their function in T helper cell 1 differentiation. For this purpose, peripheral blood mononuclear cells were activated via the T cell receptor-CD3 complex, and via CD28 as a costimulatory signal. Fast and long-term changes in intracellular zinc and calcium were monitored by flow cytometry. Further, interferon (IFN)-γ was analyzed to investigate the differentiation into T helper 1 cells. We show that fast zinc fluxes are induced via CD3. Also, the intracellular zinc concentration dramatically increases 72 h after anti-CD3 and anti-CD28 stimulation, which goes along with the high release of IFN-γ. Interestingly, we found that zinc signals can function as a costimulatory signal for T helper cell 1 differentiation when T cells are activated only via CD3. These results demonstrate the importance of zinc signaling alongside calcium signaling in T cell differentiation.
    Keywords:  T helper cell 1; differentiation; signaling; zinc
    DOI:  https://doi.org/10.3390/ijms25084302
  13. J Transl Med. 2024 Apr 24. 22(1): 384
    Deciphering the importance of culture pH on CD22 CAR T-cells characteristics.
    Michaela Prochazkova, Alexandra Dreyzin, Lipei Shao, Pam Garces, Yihua Cai, Rongye Shi, Alejandra Pelayo, Yong Soo Kim, Victoria Pham, Sue Ellen Frodigh, Shannon Fenton, Catherine Karangwa, Yan Su, Kathryn Martin, Nan Zhang, Steven L Highfill, Robert P Somerville, Nirali N Shah, David F Stroncek, Ping Jin.
       BACKGROUND: Chimeric antigen receptor (CAR) T-cells have demonstrated significant efficacy in targeting hematological malignancies, and their use continues to expand. Despite substantial efforts spent on the optimization of protocols for CAR T-cell manufacturing, critical parameters of cell culture such as pH or oxygenation are rarely actively monitored during cGMP CAR T-cell generation. A comprehensive understanding of the role that these factors play in manufacturing may help in optimizing patient-specific CAR T-cell therapy with maximum benefits and minimal toxicity.
    METHODS: This retrospective study examined cell culture supernatants from the manufacture of CAR T-cells for 20 patients with B-cell malignancies enrolled in a phase 1/2 clinical trial of anti-CD22 CAR T-cells. MetaFLEX was used to measure supernatant pH, oxygenation, and metabolites, and a Bio-Plex assay was used to assess protein levels. Correlations were assessed between the pH of cell culture media throughout manufacturing and cell proliferation as well as clinical outcomes. Next-generation sequencing was conducted to examine gene expression profiles of the final CAR T-cell products.
    RESULTS: A pH level at the lower range of normal at the beginning of the manufacturing process significantly correlated with measures of T-cell expansion and metabolism. Stable or rising pH during the manufacturing process was associated with clinical response, whereas a drop in pH was associated with non-response.
    CONCLUSIONS: pH has potential to serve as an informative factor in predicting CAR T-cell quality and clinical outcomes. Thus, its active monitoring during manufacturing may ensure a more effective CAR T-cell product.
    Keywords:  Chimeric antigen receptor (CAR) T-cells; Clinical manufacturing; Immunotherapy; pH
    DOI:  https://doi.org/10.1186/s12967-024-05197-5
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