bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–06–23
eightteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Conserved epigenetic hallmarks of T cell aging during immunity and malignancy.
  2. Tumor glucose metabolism and the T cell glycocalyx: implication for T cell function.
  3. Oleic acid enhances proliferation and calcium mobilization of CD3/CD28 activated CD4+ T cells through incorporation into membrane lipids.
  4. Generation, transcriptomic states, and clinical relevance of CX3CR1+ CD8 T cells in melanoma.
  5. Metabolic shifts during coffee consumption refresh the immune response: insight from comprehensive multiomics analysis.
  6. Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.
  7. The PP2A regulatory subunit PPP2R2A controls NAD+ biosynthesis to regulate T cell subset differentiation in systemic autoimmunity.
  8. Distinct SIV-specific CD8+ T cells in the lymph node exhibit simultaneous effector and stem-like profiles and are associated with limited SIV persistence.
  9. Intratumoral immune triads are required for immunotherapy-mediated elimination of solid tumors.
  10. SARS-CoV-2 inflammation durably imprints memory CD4 T cells.
  11. CD8+ T cell-derived Fgl2 regulates immunity in a cell-autonomous manner via ligation of FcγRIIB.
  12. Immunotoxin-mediated depletion of Gag-specific CD8+ T cells undermines natural control of Simian immunodeficiency virus.
  13. Collaboration between IL-7 and IL-15 enables adaptation of tissue-resident and circulating memory CD8 + T cells.
  14. In vitro IL-15-activated human naïve CD8+ T cells down-modulate the CD8β chain and become CD8αα T cells.
  15. Dependence on mitochondrial respiration of malignant T cells reveals a new therapeutic target for angioimmunoblastic T-cell lymphoma.
  16. Nicotinamide metabolism face-off between macrophages and fibroblasts manipulates the microenvironment in gastric cancer.
  17. Cancer stem cell-derived exosomes in CD8+ T cell exhaustion.
  18. Stem-like T cells are associated with the pathogenesis of ulcerative colitis in humans.
  1. Nat Aging. 2024 Jun 12.
    Conserved epigenetic hallmarks of T cell aging during immunity and malignancy.
    Tian Mi, Andrew G Soerens, Shanta Alli, Tae Gun Kang, Anoop Babu Vasandan, Zhaoming Wang, Vaiva Vezys, Shunsuke Kimura, Ilaria Iacobucci, Stephen B Baylin, Peter A Jones, Christopher Hiner, April Mueller, Harris Goldstein, Charles G Mullighan, Caitlin C Zebley, David Masopust, Ben Youngblood.
      Chronological aging correlates with epigenetic modifications at specific loci, calibrated to species lifespan. Such 'epigenetic clocks' appear conserved among mammals, but whether they are cell autonomous and restricted by maximal organismal lifespan remains unknown. We used a multilifetime murine model of repeat vaccination and memory T cell transplantation to test whether epigenetic aging tracks with cellular replication and if such clocks continue 'counting' beyond species lifespan. Here we found that memory T cell epigenetic clocks tick independently of host age and continue through four lifetimes. Instead of recording chronological time, T cells recorded proliferative experience through modification of cell cycle regulatory genes. Applying this epigenetic profile across a range of human T cell contexts, we found that naive T cells appeared 'young' regardless of organism age, while in pediatric patients, T cell acute lymphoblastic leukemia appeared to have epigenetically aged for up to 200 years. Thus, T cell epigenetic clocks measure replicative history and can continue to accumulate well-beyond organismal lifespan.
    DOI:  https://doi.org/10.1038/s43587-024-00649-5
  2. Front Immunol. 2024 ;15 1409238
    Tumor glucose metabolism and the T cell glycocalyx: implication for T cell function.
    Fabian Schuurmans, Kyra E Wagemans, Gosse J Adema, Lenneke A M Cornelissen.
      The T cell is an immune cell subset highly effective in eliminating cancer cells. Cancer immunotherapy empowers T cells and occupies a solid position in cancer treatment. The response rate, however, remains relatively low (<30%). The efficacy of immunotherapy is highly dependent on T cell infiltration into the tumor microenvironment (TME) and the ability of these infiltrated T cells to sustain their function within the TME. A better understanding of the inhibitory impact of the TME on T cells is crucial to improve cancer immunotherapy. Tumor cells are well described for their switch into aerobic glycolysis (Warburg effect), resulting in high glucose consumption and a metabolically distinct TME. Conversely, glycosylation, a predominant posttranslational modification of proteins, also relies on glucose molecules. Proper glycosylation of T cell receptors influences the immunological synapse between T cells and tumor cells, thereby affecting T cell effector functions including their cytolytic and cytostatic activities. This review delves into the complex interplay between tumor glucose metabolism and the glycocalyx of T cells, shedding light on how the TME can induce alterations in the T cell glycocalyx, which can subsequently influence the T cell's ability to target and eliminate tumor cells.
    Keywords:  T cell glycocalyx; glycobiology; metabolism; tumor immunity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1409238
  3. Eur J Immunol. 2024 Jun 18. e2350685
    Oleic acid enhances proliferation and calcium mobilization of CD3/CD28 activated CD4+ T cells through incorporation into membrane lipids.
    Johannes Hendrick von Hegedus, Anja J de Jong, Anna T Hoekstra, Eric Spronsen, Wahwah Zhu, Birol Cabukusta, Joanneke C Kwekkeboom, Marieke Heijink, Erik Bos, Celia R Berkers, Martin A Giera, Rene E M Toes, Andreea Ioan-Facsinay.
      Unsaturated fatty acids (UFA) are crucial for T-cell effector functions, as they can affect the growth, differentiation, survival, and function of T cells. Nonetheless, the mechanisms by which UFA affects T-cell behavior are ill-defined. Therefore, we analyzed the processing of oleic acid, a prominent UFA abundantly present in blood, adipocytes, and the fat pads surrounding lymph nodes, in CD4+ T cells. We found that exogenous oleic acid increases proliferation and enhances the calcium flux response upon CD3/CD28 activation. By using a variety of techniques, we found that the incorporation of oleic acid into membrane lipids, rather than regulation of cellular metabolism or TCR expression, is essential for its effects on CD4+ T cells. These results provide novel insights into the mechanism through which exogenous oleic acid enhances CD4+ T-cell function.
    Keywords:  CD4 T cells; Cellular proliferation; Fatty acids; Immune regulation; Metabolomics; Oleic acid; TCR
    DOI:  https://doi.org/10.1002/eji.202350685
  4. Cancer Res Commun. 2024 Jun 15.
    Generation, transcriptomic states, and clinical relevance of CX3CR1+ CD8 T cells in melanoma.
    Hirohito Ishigaki, Takayoshi Yamauchi, Mark D Long, Toshifumi Hoki, Yuta Yamamoto, Takaaki Oba, Fumito Ito.
      Recent progress in single-cell profiling technologies has revealed significant phenotypic and transcriptional heterogeneity in tumor-infiltrating CD8+ T cells. However, the transition between the different states of intratumoral antigen-specific CD8+ T cells remains elusive. Here, we sought to examine the generation, transcriptomic states, and the clinical relevance of melanoma-infiltrating CD8+ T cells expressing a chemokine receptor and T-cell differentiation marker, CX3C chemokine receptor 1 (CX3CR1). Analysis of single-cell datasets revealed two distinct human melanoma-infiltrating CD8+ T-cell clusters expressing CX3CR1 and PDCD1, whereas both clusters expressed genes associated with effector T cell function. No obvious impact of CX3CR1 expression in melanoma on the response to immune checkpoint inhibitor therapy was observed while increased pre- and on-treatment frequency of a CD8+ T-cell cluster expressing high levels of exhaustion markers was associated with poor response to the treatment. Adoptively transferred antigen-specific CX3CR1- CD8+ T cells differentiated into the CX3CR1+ subset in mice treated with FTY720, which inhibits lymphocyte egress from secondary lymphoid tissues, suggesting the intratumoral generation of CX3CR1+ CD8+ T cells rather than their trafficking from secondary lymphoid organs. Furthermore, analysis of adoptively transferred antigen-specific CD8+ T cells, in which the Cx3cr1 gene was replaced with a marker gene confirmed that CX3CR1+ CD8+ T cells could directly differentiate from the intratumoral CX3CR1- subset. These findings highlight that tumor antigen-specific CX3CR1- CD8+ T cells can fully differentiate outside the secondary lymphoid organs, and generate CX3CR1+ CD8+ T cells in the tumor microenvironment, which are distinct from CD8+ T cells that express markers of exhaustion.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-24-0199
  5. MedComm (2020). 2024 Jul;5(7): e617
    Metabolic shifts during coffee consumption refresh the immune response: insight from comprehensive multiomics analysis.
    Pinglang Ruan, Ming Yang, Xinyi Lv, Kai Shen, Yiran Chen, Hongli Li, Di Zhao, Jianhua Huang, Yang Xiao, Weijun Peng, Haijing Wu, Qianjin Lu.
      Coffee, a widely consumed beverage, has shown benefits for human health but lacks sufficient basic and clinical evidence to fully understand its impacts and mechanisms. Here, we conducted a cross-sectional observational study of coffee consumption and a 1-month clinical trial in humans. We found that coffee consumption significantly reshaped the immune system and metabolism, including reduced levels of inflammatory factors and a reduced frequency of senescent T cells. The frequency of senescent T cells and the levels of the senescence-associated secretory phenotype were lower in both long-term coffee consumers and new coffee consumers than in coffee nondrinking subjects, suggesting that coffee has anti-immunosenescence effects. Moreover, coffee consumption downregulated the activities of the The Janus kinase/signal transduction and activator of transcription (JAK/STAT) and mitogen-activated protein kinases (MAPK) signaling pathways and reduced systemic proinflammatory cytokine levels. Mechanistically, coffee-associated metabolites, such as 1-methylxanthine, 3-methylxanthine, paraxanthine, and ceramide, reduced the frequency of senescent CD4+CD57+ T cells in vitro. Finally, in vivo, coffee intake alleviated inflammation and immunosenescence in imiquimod-induced psoriasis-like mice. Our results provide novel evidence of the anti-inflammatory and anti-immunosenescence effects of coffee, suggesting that coffee consumption could be considered a healthy habit.
    Keywords:  anti‐immunosenescence; anti‐inflammatory; coffee consumption; coffee‐related metabolism; immune remodeling
    DOI:  https://doi.org/10.1002/mco2.617
  6. Dev Cell. 2024 May 20. pii: S1534-5807(24)00295-8. [Epub ahead of print]
    Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.
    George Kelly, Tetsushi Kataura, Johan Panek, Gailing Ma, Hanna Salmonowicz, Ashley Davis, Hannah Kendall, Charlotte Brookes, Daniel Moscoh Ayine-Tora, Peter Banks, Glyn Nelson, Laura Dobby, Patricia R Pitrez, Laura Booth, Lydia Costello, Gavin D Richardson, Penny Lovat, Stefan Przyborski, Lino Ferreira, Laura Greaves, Karolina Szczepanowska, Thomas von Zglinicki, Satomi Miwa, Max Brown, Michael Flagler, John E Oblong, Charles C Bascom, Bernadette Carroll, Jóhannes Reynisson, Viktor I Korolchuk.
      Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. However, the molecular mechanisms and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. Here, we demonstrated that primary human cells maintain highly active basal mitophagy initiated by mitochondrial superoxide signaling. Mitophagy was found to be mediated by PINK1/Parkin-dependent pathway involving p62 as a selective autophagy receptor (SAR). Importantly, this pathway was suppressed upon the induction of cellular senescence and in naturally aged cells, leading to a robust shutdown of mitophagy. Inhibition of mitophagy in proliferating cells was sufficient to trigger the senescence program, while reactivation of mitophagy was necessary for the anti-senescence effects of NAD precursors or rapamycin. Furthermore, reactivation of mitophagy by a p62-targeting small molecule rescued markers of cellular aging, which establishes mitochondrial quality control as a promising target for anti-aging interventions.
    Keywords:  PINK1; Parkin; aging; autophagy; mitophagy; nicotinamide; nicotinamide riboside; p62; rapamycin; redox; senescence
    DOI:  https://doi.org/10.1016/j.devcel.2024.04.020
  7. Cell Rep. 2024 Jun 17. pii: S2211-1247(24)00707-1. [Epub ahead of print]43(7): 114379
    The PP2A regulatory subunit PPP2R2A controls NAD+ biosynthesis to regulate T cell subset differentiation in systemic autoimmunity.
    Wenliang Pan, Maria G Tsokos, Marc Scherlinger, Wei Li, George C Tsokos.
      The protein phosphatase 2A (PP2A) regulatory subunit PPP2R2A is involved in the regulation of immune response. We report that lupus-prone mice with T cells deficient in PPP2R2A display less autoimmunity and nephritis. PPP2R2A deficiency promotes NAD+ biosynthesis through the nicotinamide riboside (NR)-directed salvage pathway in T cells. NR inhibits murine Th17 and promotes Treg cell differentiation, in vitro, by PΑRylating histone H1.2 and causing its reduced occupancy in the Foxp3 loci and increased occupancy in the Il17a loci, leading to increased Foxp3 and decreased Il17a transcription. NR treatment suppresses disease in MRL.lpr mice and restores NAD+-dependent poly [ADP-ribose] polymerase 1 (PARP1) activity in CD4 T cells from patients with systemic lupus erythematosus (SLE), while reducing interferon (IFN)-γ and interleukin (IL)-17 production. We conclude that PPP2R2A controls the level of NAD+ through the NR-directed salvage pathway and promotes systemic autoimmunity. Translationally, NR suppresses lupus nephritis in mice and limits the production of proinflammatory cytokines by SLE T cells.
    Keywords:  CP: Immunology; CP: Metabolism; NAD(+); NR; PARP1; PP2A; PPP2R2A; Th17; Treg; histone H1.2; systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.celrep.2024.114379
  8. Nat Immunol. 2024 Jun 17.
    Distinct SIV-specific CD8+ T cells in the lymph node exhibit simultaneous effector and stem-like profiles and are associated with limited SIV persistence.
    Zachary Strongin, Laurence Raymond Marchand, Claire Deleage, M Betina Pampena, Maria Andrea Cardenas, Christian Michel Beusch, Timothy N Hoang, Elizabeth A Urban, Mael Gourves, Kevin Nguyen, Gregory K Tharp, Stacey Lapp, Andrew R Rahmberg, Justin Harper, Perla M Del Rio Estrada, Mauricio Gonzalez-Navarro, Fernanda Torres-Ruiz, Yara Andrea Luna-Villalobos, Santiago Avila-Rios, Gustavo Reyes-Teran, Rafick Sekaly, Guido Silvestri, Deanna A Kulpa, Asier Saez-Cirion, Jason M Brenchley, Steven E Bosinger, David Ezra Gordon, Michael R Betts, Haydn T Kissick, Mirko Paiardini.
      Human immunodeficiency virus (HIV) cure efforts are increasingly focused on harnessing CD8+ T cell functions, which requires a deeper understanding of CD8+ T cells promoting HIV control. Here we identifiy an antigen-responsive TOXhiTCF1+CD39+CD8+ T cell population with high expression of inhibitory receptors and low expression of canonical cytolytic molecules. Transcriptional analysis of simian immunodeficiency virus (SIV)-specific CD8+ T cells and proteomic analysis of purified CD8+ T cell subsets identified TOXhiTCF1+CD39+CD8+ T cells as intermediate effectors that retained stem-like features with a lineage relationship with terminal effector T cells. TOXhiTCF1+CD39+CD8+ T cells were found at higher frequency than TCF1-CD39+CD8+ T cells in follicular microenvironments and were preferentially located in proximity of SIV-RNA+ cells. Their frequency was associated with reduced plasma viremia and lower SIV reservoir size. Highly similar TOXhiTCF1+CD39+CD8+ T cells were detected in lymph nodes from antiretroviral therapy-naive and antiretroviral therapy-suppressed people living with HIV, suggesting this population of CD8+ T cells contributes to limiting SIV and HIV persistence.
    DOI:  https://doi.org/10.1038/s41590-024-01875-0
  9. Cancer Cell. 2024 Jun 19. pii: S1535-6108(24)00193-4. [Epub ahead of print]
    Intratumoral immune triads are required for immunotherapy-mediated elimination of solid tumors.
    Gabriel Espinosa-Carrasco, Edison Chiu, Aurora Scrivo, Paul Zumbo, Asim Dave, Doron Betel, Sung Wook Kang, Hee-Jin Jang, Matthew D Hellmann, Bryan M Burt, Hyun-Sung Lee, Andrea Schietinger.
      Tumor-specific CD8+ T cells are frequently dysfunctional and unable to halt tumor growth. We investigated whether tumor-specific CD4+ T cells can be enlisted to overcome CD8+ T cell dysfunction within tumors. We find that the spatial positioning and interactions of CD8+ and CD4+ T cells, but not their numbers, dictate anti-tumor responses in the context of adoptive T cell therapy as well as immune checkpoint blockade (ICB): CD4+ T cells must engage with CD8+ T cells on the same dendritic cell during the effector phase, forming a three-cell-type cluster (triad) to license CD8+ T cell cytotoxicity and cancer cell elimination. When intratumoral triad formation is disrupted, tumors progress despite equal numbers of tumor-specific CD8+ and CD4+ T cells. In patients with pleural mesothelioma treated with ICB, triads are associated with clinical responses. Thus, CD4+ T cells and triads are required for CD8+ T cell cytotoxicity during the effector phase and tumor elimination.
    Keywords:  CD4 T cell; CD8 T cell; Cancer; adoptive T cell transfer; cancer immunotherapy; dendritic cell; immune checkpoint blockade; triad; tumor; tumor antigen
    DOI:  https://doi.org/10.1016/j.ccell.2024.05.025
  10. Sci Immunol. 2024 Jun 21. 9(96): eadj8526
    SARS-CoV-2 inflammation durably imprints memory CD4 T cells.
    Sophie L Gray-Gaillard, Sabrina M Solis, Han M Chen, Clarice Monteiro, Grace Ciabattoni, Marie I Samanovic, Amber R Cornelius, Tijaana Williams, Emilie Geesey, Miguel Rodriguez, Mila Brum Ortigoza, Ellie N Ivanova, Sergei B Koralov, Mark J Mulligan, Ramin Sedaghat Herati.
      Memory CD4 T cells are critical to human immunity, yet it is unclear whether viral inflammation during memory formation has long-term consequences. Here, we compared transcriptional and epigenetic landscapes of Spike (S)-specific memory CD4 T cells in 24 individuals whose first exposure to S was via SARS-CoV-2 infection or mRNA vaccination. Nearly 2 years after memory formation, S-specific CD4 T cells established by infection remained enriched for transcripts related to cytotoxicity and for interferon-stimulated genes, likely because of a chromatin accessibility landscape altered by inflammation. Moreover, S-specific CD4 T cells primed by infection had reduced proliferative capacity in vitro relative to vaccine-primed cells. Furthermore, the transcriptional state of S-specific memory CD4 T cells was minimally altered by booster immunization and/or breakthrough infection. Thus, infection-associated inflammation durably imprints CD4 T cell memory, which affects the function of these cells and may have consequences for long-term immunity.
    DOI:  https://doi.org/10.1126/sciimmunol.adj8526
  11. Nat Commun. 2024 Jun 20. 15(1): 5280
    CD8+ T cell-derived Fgl2 regulates immunity in a cell-autonomous manner via ligation of FcγRIIB.
    Kelsey B Bennion, Danya Liu, Abdelhameed S Dawood, Megan M Wyatt, Katie L Alexander, Mohamed S Abdel-Hakeem, Chrystal M Paulos, Mandy L Ford.
      The regulatory circuits dictating CD8+ T cell responsiveness versus exhaustion during anti-tumor immunity are incompletely understood. Here we report that tumor-infiltrating antigen-specific PD-1+ TCF-1- CD8+ T cells express the immunosuppressive cytokine Fgl2. Conditional deletion of Fgl2 specifically in mouse antigen-specific CD8+ T cells prolongs CD8+ T cell persistence, suppresses phenotypic and transcriptomic signatures of T cell exhaustion, and improves control of the tumor. In a mouse model of chronic viral infection, PD-1+ CD8+ T cell-derived Fgl2 also negatively regulates virus-specific T cell responses. In humans, CD8+ T cell-derived Fgl2 is associated with poorer survival in patients with melanoma. Mechanistically, the dampened responsiveness of WT Fgl2-expressing CD8+ T cells, when compared to Fgl2-deficient CD8+ T cells, is underpinned by the cell-intrinsic interaction of Fgl2 with CD8+ T cell-expressed FcγRIIB and concomitant caspase 3/7-mediated apoptosis. Our results thus illuminate a cell-autonomous regulatory axis by which PD-1+ CD8+ T cells both express the receptor and secrete its ligand in order to mediate suppression of anti-tumor and anti-viral immunity.
    DOI:  https://doi.org/10.1038/s41467-024-49475-8
  12. JCI Insight. 2024 Jun 11. pii: e174168. [Epub ahead of print]
    Immunotoxin-mediated depletion of Gag-specific CD8+ T cells undermines natural control of Simian immunodeficiency virus.
    Jennifer Simpson, Carly E Starke, Alexandra M Ortiz, Amy Ransier, Sam Darko, Sian Llewellyn-Lacey, Christine M Fennessey, Brandon F Keele, Daniel C Douek, David A Price, Jason M Brenchley.
      Antibody-mediated depletion studies have demonstrated that CD8+ T cells are required for effective immune control of SIV. However, this approach is confounded by several factors, including reactive CD4+ T cell proliferation, and further provides no specificity information. We circumvented these limitations by selectively depleting CD8+ T cells specific for the Gag epitope CTPYDINQM (CM9) via the administration of immunotoxin-conjugated tetrameric complexes of CM9/Mamu-A*01. Immunotoxin administration effectively depleted circulating but not tissuelocalized CM9-specific CD8+ T cells, akin to the bulk depletion pattern observed with antibodies directed against CD8. However, we found no evidence to indicate that circulating CM9-specific CD8+ T cells suppressed viral replication in Mamu-A*01+ rhesus macaques during acute or chronic progressive infection with a pathogenic strain of SIV. This observation extended to macaques with established infection during and after continuous antiretroviral therapy. In contrast, natural controller macaques experienced dramatic increases in plasma viremia after immunotoxin administration, highlighting the importance of CD8+ T cell-mediated immunity against CM9. Collectively, these data showed that CM9-specific CD8+ T cells were necessary but not sufficient for robust immune control of SIV in a nonhuman primate model and, more generally, validated an approach that could inform the design of next-generation vaccines against HIV-1.
    Keywords:  AIDS/HIV; Adaptive immunity
    DOI:  https://doi.org/10.1172/jci.insight.174168
  13. bioRxiv. 2024 Jun 03. pii: 2024.05.31.596695. [Epub ahead of print]
    Collaboration between IL-7 and IL-15 enables adaptation of tissue-resident and circulating memory CD8 + T cells.
    Nicholas N Jarjour, Talia S Dalzell, Nicholas J Maurice, Kelsey M Wanhainen, Changwei Peng, Taylor A DePauw, Katharine E Block, William J Valente, K Maude Ashby, David Masopust, Stephen C Jameson.
      Interleukin-7 (IL-7) is considered a critical regulator of memory CD8 + T cell homeostasis, but this is primarily based on analysis of circulating and not tissue-resident memory (T RM ) subsets. Furthermore, the cell-intrinsic requirement for IL-7 signaling during memory homeostasis has not been directly tested. Using inducible deletion, we found that Il7ra loss had only a modest effect on persistence of circulating memory and T RM subsets and that IL-7Rα was primarily required for normal basal proliferation. Loss of IL-15 signaling imposed heightened IL-7Rα dependence on memory CD8 + T cells, including T RM populations previously described as IL-15-independent. In the absence of IL-15 signaling, IL-7Rα was upregulated, and loss of IL-7Rα signaling reduced proliferation in response to IL-15, suggesting cross-regulation in memory CD8 + T cells. Thus, across subsets and tissues, IL-7 and IL-15 act in concert to support memory CD8 + T cells, conferring resilience to altered availability of either cytokine.
    Highlights: Tissue-resident and circulating memory CD8 + T cells modestly decline after loss of IL-7Rα IL-7Rα is required for normal self-renewal of memory CD8 + T cells Combined loss of IL-7 and IL-15 causes a profound defect across memory CD8 + T cell subsets Cross-regulation of IL-7 and IL-15 signaling occurs in memory CD8 + T cells.
    Abstract Figure:
    DOI:  https://doi.org/10.1101/2024.05.31.596695
  14. Front Immunol. 2024 ;15 1252439
    In vitro IL-15-activated human naïve CD8+ T cells down-modulate the CD8β chain and become CD8αα T cells.
    André J Esgalhado, Débora Reste-Ferreira, Sandra Weinhold, Markus Uhrberg, Elsa M Cardoso, Fernando A Arosa.
      Antigen-driven human effector-memory CD8+ T cells expressing low levels of the CD8β chain have been previously described. However, little is known on a possible antigen-independent trigger. We have examined the impact that IL-15 has on the expression of CD8β on purified human naïve CD8+ T cells after CFSE labeling and culture with IL-15. As expected, IL-15 induced naïve CD8+ T cells to proliferate and differentiate. Remarkably, the process was associated with a cell-cycle dependent down-modulation of CD8β from the cell surface, leading to the generation of CD8αβlow and CD8αβ- (i.e., CD8αα) T cells. In contrast, expression of the CD8α chain remained steady or even increased. Neither IL-2 nor IL-7 reproduced the effect of IL-15. Determination of mRNA levels for CD8α and CD8β isoforms by qPCR revealed that IL-15 promoted a significant decrease in mRNA levels of the CD8β M-4 isoform, while levels of the M-1/M-2 isoforms and of CD8α increased. Noteworthy, CD8+ T cell blasts obtained after culture of CD8+ T cells with IL-15 showed a cell-cycle dependent increase in the level of the tyrosine kinase Lck, when compared to CD8+ T cells at day 0. This study has shown for the first time that IL-15 generates CD8αα+αβlow and CD8αα+αβ- T cells containing high levels of Lck, suggesting that they may be endowed with unique functional features.
    Keywords:  CD8α chain; CD8β chain; IL-15; downregulation; effector-memory CD8+ T cells; naïve CD8+ T cells
    DOI:  https://doi.org/10.3389/fimmu.2024.1252439
  15. Cell Death Discov. 2024 Jun 19. 10(1): 292
    Dependence on mitochondrial respiration of malignant T cells reveals a new therapeutic target for angioimmunoblastic T-cell lymphoma.
    Adrien Krug, Rana Mhaidly, Marie Tosolini, Laura Mondragon, Gamze Tari, Adriana Martinez Turtos, Rachel Paul-Bellon, Vahid Asnafi, Sandrine Marchetti, Léa Di Mascio, Marion Travert, Frédéric Bost, Emmanuel Bachy, Rafael J Argüello, Jean-Jacques Fournié, Philippe Gaulard, François Lemonnier, Jean-Ehrland Ricci, Els Verhoeyen.
      Cancer metabolic reprogramming has been recognized as one of the cancer hallmarks that promote cell proliferation, survival, as well as therapeutic resistance. Up-to-date regulation of metabolism in T-cell lymphoma is poorly understood. In particular, for human angioimmunoblastic T-cell lymphoma (AITL) the metabolic profile is not known. Metabolic intervention could help identify new treatment options for this cancer with very poor outcomes and no effective medication. Transcriptomic analysis of AITL tumor cells, identified that these cells use preferentially mitochondrial metabolism. By using our preclinical AITL mouse model, mimicking closely human AITL features, we confirmed that T follicular helper (Tfh) tumor cells exhibit a strong enrichment of mitochondrial metabolic signatures. Consistent with these results, disruption of mitochondrial metabolism using metformin or a mitochondrial complex I inhibitor such as IACS improved the survival of AITL lymphoma-bearing mice. Additionally, we confirmed a selective elimination of the malignant human AITL T cells in patient biopsies upon mitochondrial respiration inhibition. Moreover, we confirmed that diabetic patients suffering from T-cell lymphoma, treated with metformin survived longer as compared to patients receiving alternative treatments. Taking together, our findings suggest that targeting the mitochondrial metabolic pathway could be a clinically efficient approach to inhibit aggressive cancers such as peripheral T-cell lymphoma.
    DOI:  https://doi.org/10.1038/s41420-024-02061-9
  16. Cell Metab. 2024 Jun 12. pii: S1550-4131(24)00189-X. [Epub ahead of print]
    Nicotinamide metabolism face-off between macrophages and fibroblasts manipulates the microenvironment in gastric cancer.
    Yu Jiang, Yawen Wang, Guofeng Chen, Fei Sun, Qijing Wu, Qiong Huang, Dongqiang Zeng, Wenjun Qiu, Jiao Wang, Zhiqi Yao, Bishan Liang, Shaowei Li, Jianhua Wu, Na Huang, Yuanyuan Wang, Jingsong Chen, Xiaohui Zhai, Li Huang, Beibei Xu, Masami Yamamoto, Tetsuya Tsukamoto, Sachiyo Nomura, Wangjun Liao, Min Shi.
      Immune checkpoint blockade has led to breakthroughs in the treatment of advanced gastric cancer. However, the prominent heterogeneity in gastric cancer, notably the heterogeneity of the tumor microenvironment, highlights the idea that the antitumor response is a reflection of multifactorial interactions. Through transcriptomic analysis and dynamic plasma sample analysis, we identified a metabolic "face-off" mechanism within the tumor microenvironment, as shown by the dual prognostic significance of nicotinamide metabolism. Specifically, macrophages and fibroblasts expressing the rate-limiting enzymes nicotinamide phosphoribosyltransferase and nicotinamide N-methyltransferase, respectively, regulate the nicotinamide/1-methylnicotinamide ratio and CD8+ T cell function. Mechanistically, nicotinamide N-methyltransferase is transcriptionally activated by the NOTCH pathway transcription factor RBP-J and is further inhibited by macrophage-derived extracellular vesicles containing nicotinamide phosphoribosyltransferase via the SIRT1/NICD axis. Manipulating nicotinamide metabolism through autologous injection of extracellular vesicles restored CD8+ T cell cytotoxicity and the anti-PD-1 response in gastric cancer.
    Keywords:  crosstalk; face-off; fibroblast; gastric cancer; immune checkpoint blockade; macrophage; nicotinamide metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2024.05.013
  17. Int Immunopharmacol. 2024 Jun 17. pii: S1567-5769(24)01030-0. [Epub ahead of print]137 112509
    Cancer stem cell-derived exosomes in CD8+ T cell exhaustion.
    Amir Gholami.
      Tumor-derived extracellular vesicles (EVs) are one of the most important ways of intercellular communication and signaling. Cancer stem cells (CSCs) secrete EVs to modulate immune checkpoint molecules and evade immune surveillance. Activated CD8+ T cells known as cytotoxic T lymphocytes (CTLs) are the most powerful anti-cancer adaptive cells. Their activity is compromised upon encountering cells and signaling within the tumor microenvironment (TME), resulting in hyporesponsiveness called exhaustion. CSC-derived exosomes express programmed death ligand-1 (PD-L1) and upregulate programmed death-1 (PD-1) on CD8+ T cells to promote their exhaustion. PD-L1 expression on tumor-derived exosomes appears to be induced by CSC-derived exosomes containing transforming growth factor (TGF)-β. Tenascin-C is another constituent of CSC exosomes that acts on mammalian target of rapamycin (mTOR) signaling in T cells. Glycolysis is a metabolic event promoted by the inducing effect of CSC-derived exosomes on hypoxia-inducible factor-1α (HIF-1α). CSC interaction with CD8+ T cells is even more complex as the CSC-derived exosomes contain Notch1 to stimulate stemness in non-tumor cells, and the inducible effect of Notch1 on PD-1 promotes CD8+ T cell exhaustion. CSC exosome targeting has not been extensively studied yet. Advances in the field will open up new therapeutic windows and shape the future of cancer immunotherapy.
    Keywords:  CD8(+) T cell; Cancer stem cell; Exhaustion; Exosome; Programmed death-1 (PD-1)
    DOI:  https://doi.org/10.1016/j.intimp.2024.112509
  18. Nat Immunol. 2024 Jun 19.
    Stem-like T cells are associated with the pathogenesis of ulcerative colitis in humans.
    Yingcong Li, Ciro Ramírez-Suástegui, Richard Harris, Francisco Emmanuel Castañeda-Castro, Gabriel Ascui, Tamara Pérez-Jeldres, Alejandro Diaz, Carla Morong, Daniel A Giles, Jiani Chai, Gregory Seumois, Tilman Sanchez-Elsner, Fraser Cummings, Mitchell Kronenberg, Pandurangan Vijayanand.
      To understand the role of T cells in the pathogenesis of ulcerative colitis (UC), we analyzed colonic T cells isolated from patients with UC and controls. Here we identified colonic CD4+ and CD8+ T lymphocyte subsets with gene expression profiles resembling stem-like progenitors, previously reported in several mouse models of autoimmune disease. Stem-like T cells were increased in inflamed areas compared to non-inflamed regions from the same patients. Furthermore, TCR sequence analysis indicated stem-like T cells were clonally related to proinflammatory T cells, suggesting their involvement in sustaining effectors that drive inflammation. Using an adoptive transfer colitis model in mice, we demonstrated that CD4+ T cells deficient in either BCL-6 or TCF1, transcription factors that promote T cell stemness, had decreased colon T cells and diminished pathogenicity. Our results establish a strong association between stem-like T cell populations and UC pathogenesis, highlighting the potential of targeting this population to improve clinical outcomes.
    DOI:  https://doi.org/10.1038/s41590-024-01860-7
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