bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–11–10
twelve papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay.
  2. Food for thought: Nutrient metabolism controlling early T cell development.
  3. Applying metabolic control strategies to engineered T cell cancer therapies.
  4. Mitochondrial respiratory capacity is not altered in aging rat brains with or without memory impairment.
  5. T cell landscape in the microenvironment of human solid tumors.
  6. The role of mitochondrial transfer in the suppression of CD8+ T cell responses by Mesenchymal stem cells.
  7. Maturation and persistence of CAR T cells derived from human pluripotent stem cells via chemical inhibition of G9a/GLP.
  8. Coenzyme A fueling with pantethine limits autoreactive T cell pathogenicity in experimental neuroinflammation.
  9. MitoTempo treatment as an approach to cure persistent viral infections?
  10. Acute exercise boosts NAD+ metabolism of human peripheral blood mononuclear cells.
  11. Metabolite signatures of chronological age, aging, survival, and longevity.
  12. Flotillin-2 dampens T cell antigen-sensitivity and functionality.
  1. Cell Rep Med. 2024 Oct 29. pii: S2666-3791(24)00551-2. [Epub ahead of print] 101804
    Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay.
    Tristan Tay, Gayathri Bommakanti, Elizabeth Jaensch, Aparna Gorthi, Iswarya Karapa Reddy, Yan Hu, Ruochi Zhang, Aatman S Doshi, Sin Lih Tan, Verena Brucklacher-Waldert, Laura Prickett, James Kurasawa, Michael Glen Overstreet, Steven Criscione, Jason Daniel Buenrostro, Deanna A Mele.
      In cancer, chronic antigen stimulation drives effector T cells to exhaustion, limiting the efficacy of T cell therapies. Recent studies have demonstrated that epigenetic rewiring governs the transition of T cells from effector to exhausted states and makes a subset of exhausted T cells non-responsive to PD1 checkpoint blockade. Here, we describe an antigen-specific assay for T cell exhaustion that generates T cells phenotypically and transcriptionally similar to those found in human tumors. We perform a screen of human epigenetic regulators, identifying IKZF1 as a driver of T cell exhaustion. We determine that the IKZF1 degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers and preserving the binding of AP-1, NF-κB, and NFAT. Thus, our study uncovers a role for IKZF1 as a driver of T cell exhaustion through epigenetic modulation, providing a rationale for the use of iberdomide in solid tumors to prevent T cell exhaustion.
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101804
  2. Bioessays. 2024 Nov 06. e2400179
    Food for thought: Nutrient metabolism controlling early T cell development.
    Guy Werlen, Tatiana Hernandez, Estela Jacinto.
      T cells develop in the thymus by expressing a diverse repertoire of either αβ- or γδ-T cell receptors (TCR). While many studies have elucidated how TCR signaling and gene expression control T cell ontogeny, the role of nutrient metabolism is just emerging. Here, we discuss how metabolic reprogramming and nutrient availability impact the fate of developing thymic T cells. We focus on how the PI3K/mTOR signaling mediates various extracellular inputs and how this signaling pathway controls metabolic rewiring during highly proliferative and anabolic developmental stages. We highlight the role of the hexosamine biosynthetic pathway that generates metabolites that are utilized for N- and O-linked glycosylation of proteins and how it impacts TCR expression during T cell ontogeny. We consider the dichotomy in metabolic needs during αβ- versus γδ-T cell lineage commitment as well as how metabolism is also coupled to molecular signaling that controls cell fate.
    Keywords:  PI3K/mTOR signaling; glycosylation; hexosamine biosynthesis; mTORC1/mTORC2; nutrient metabolism; thymic T cell development; αβ‐ and γδ‐T cells
    DOI:  https://doi.org/10.1002/bies.202400179
  3. Metab Eng. 2024 Oct 25. pii: S1096-7176(24)00137-X. [Epub ahead of print]
    Applying metabolic control strategies to engineered T cell cancer therapies.
    Andrea C Fox, John Blazeck.
      Chimeric antigen receptor (CAR) T cells are an engineered immunotherapy that express synthetic receptors to recognize and kill cancer cells. Despite their success in treating hematologic cancers, CAR T cells have limited efficacy against solid tumors, in part due to the altered immunometabolic profile within the tumor environment, which hinders T cell proliferation, infiltration, and anti-tumor activity. For instance, CAR T cells must compete for essential nutrients within tumors, while resisting the impacts of immunosuppressive metabolic byproducts. In this review, we will describe the altered metabolic features within solid tumors that contribute to immunosuppression of CAR T cells. We'll discuss how overexpression of key metabolic enzymes can enhance the ability of CAR T cells to resist corresponding tumoral metabolic changes or even revert the metabolic profile of a tumor to a less inhibitory state. In addition, metabolic remodeling is intrinsically linked to T cell activity, differentiation, and function, such that metabolic engineering strategies can also promote establishment of more or less efficacious CAR T cell phenotypes. Overall, we will show how applying metabolic engineering strategies holds significant promise to improve CAR T cells for the treatment of solid tumors.
    Keywords:  CAR T cell therapies; Cellular engineering; Immunotherapy; Metabolic engineering; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ymben.2024.10.009
  4. MicroPubl Biol. 2024 ;2024
    Mitochondrial respiratory capacity is not altered in aging rat brains with or without memory impairment.
    Pamela J Yao, Jeffrey M Long, Peter R Rapp, Dimitrios Kapogiannis.
      Mitochondria are essential for supporting the high metabolic demands that are required for brain function. Impairments in mitochondria have been linked to age-related decline in brain functions. Here, we investigate whether the mitochondrial respiratory capacity of brain cells is changed in cognitive aging. We used a rat model of normal cognitive aging and analyzed mitochondrial oxidative phosphorylation in frozen brain samples. Mitochondrial oxygen consumption rate analysis of the frontal cortex did not show any differences between young rats and aged rats with either intact memory or impaired spatial memory. Mitochondrial ATP synthase activity and quantity also did not differ between young and aged rats. These results suggest that the total level of mitochondrial respiratory capacity is preserved in the frontal cortex of aged rats and may not explain aging-associated cognitive impairment.
    DOI:  https://doi.org/10.17912/micropub.biology.001359
  5. Immunol Lett. 2024 Oct 31. pii: S0165-2478(24)00116-0. [Epub ahead of print]270 106942
    T cell landscape in the microenvironment of human solid tumors.
    Enrico Maggi, Enrico Munari, Nadine Landolina, Francesca Romana Mariotti, Bruno Azzarone, Lorenzo Moretta.
      T cells are the main effectors involved in anti-tumor immunity, mediating most of the adaptive response towards cancer. After priming in lymph nodes, tumor antigens-specific naïve T lymphocytes proliferate and differentiate into effector CD4+ and CD8+ T cells that migrate from periphery into tumor sites aiming to eliminate cancer cells. Then while most effector T cells die, a small fraction persists and recirculates as long-lived memory T cells which generate enhanced immune responses when re-encountering the same antigen. A number of T (and non-T) cell subsets, stably resides in non-lymphoid peripheral tissues and may provide rapid immune response independently of T cells recruited from blood, against the reemergence of cancer cells. When tumor grows, however, tumor cells have evaded immune surveillance of effector cells (NK and CTL cells) which are exhausted, thus favoring the local expansion of T (and non-T) regulatory cells. In this review, the current knowledge of features of T cells present in the tumor microenvironment (TME) of solid adult and pediatric tumors, the mechanisms upregulating immune-checkpoint molecules and transcriptional and epigenetic landscapes leading to dysfunction and exhaustion of T effector cells are reviewed. The interaction of T cells with cancer- or TME non-neoplastic cells and their secreted molecules shape the T cell profile compromising the intrinsic plasticity of T cells and, therefore, favoring immune evasion. In this phase regulatory T cells contribute to maintain a high immunosuppressive TME thus facilitating tumor cell proliferation and metastatic spread. Despite the advancements of cancer immunotherapy, many tumors are unresponsive to immune checkpoint inhibitors, or therapeutical vaccines or CAR T cell-based adoptive therapy: some novel strategies to improve these T cell-based treatments are lastly proposed.
    Keywords:  Immunosuppression; Immunotherapy of tumors; Pediatric and adult Solid tumors; T effector cells; T regulatory cells; Tumor infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.imlet.2024.106942
  6. Stem Cell Res Ther. 2024 Nov 04. 15(1): 394
    The role of mitochondrial transfer in the suppression of CD8+ T cell responses by Mesenchymal stem cells.
    Loic Vaillant, Waseem Akhter, Jean Nakhle, Matthieu Simon, Martin Villalba, Christian Jorgensen, Marie-Luce Vignais, Javier Hernandez.
       BACKGROUND: . CD8+ Cytotoxic T lymphocytes play a key role in the pathogenesis of autoimmune diseases and clinical conditions such as graft versus host disease and graft rejection. Mesenchymal Stromal Cells (MSCs) are multipotent cells with tissue repair and immunomodulatory capabilities. Since they are able to suppress multiple pathogenic immune responses, MSCs have been proposed as a cellular therapy for the treatment of immune-mediated diseases. However, the mechanisms underlying their immunosuppressive properties are not yet fully understood. MSCs have the remarkable ability to sense tissue injury and inflammation and respond by donating their own mitochondria to neighboring cells. Whether mitochondrial transfer has any role in the repression of CD8+ responses is unknown.
    METHODS AND RESULTS: . We have utilized CD8+ T cells from Clone 4 TCR transgenic mice that differentiate into effector cells upon activation in vitro and in vivo to address this question. Allogeneic bone marrow derived MSCs, co-cultured with activated Clone 4 CD8+ T cells, decreased their expansion, the production of the effector cytokine IFNγ and their diabetogenic potential in vivo. Notably, we found that during this interaction leading to suppression, MSCs transferred mitochondria to CD8+ T cells as evidenced by FACS and confocal microscopy. Transfer of MSC mitochondria to Clone 4 CD8+ T cells also resulted in decreased expansion and production of IFNγ upon activation. These effects overlapped and were additive with those of prostaglandin E2 secreted by MSCs. Furthermore, preventing mitochondrial transfer in co-cultures diminished the ability of MSCs to inhibit IFNγ production. Finally, we demonstrated that both MSCs and MSC mitochondria downregulated T-bet and Eomes expression, key transcription factors for CTL differentiation, on activated CD8+ T cells.
    CONCLUSION: . In this report we showed that MSCs are able to interact with CD8+ T cells and transfer them their mitochondria. Mitochondrial transfer contributed to the global suppressive effect of MSCs on CD8+ T cell activation by downregulating T-bet and Eomes expression resulting in impaired IFNγ production of activated CD8+ T cells.
    Keywords:  Autoimmunity; CD8+ T cells; Immunotherapy; Mesenchymal stem/stromal cells; Mitochondrial transfer
    DOI:  https://doi.org/10.1186/s13287-024-03980-1
  7. Cell Stem Cell. 2024 Nov 01. pii: S1934-5909(24)00366-7. [Epub ahead of print]
    Maturation and persistence of CAR T cells derived from human pluripotent stem cells via chemical inhibition of G9a/GLP.
    Ran Jing, Marcelo Falchetti, Tianxiao Han, Mohamad Najia, Luca T Hensch, Eleanor Meader, Edroaldo Lummertz da Rocha, Martin Kononov, Stephanie Wang, Trevor Bingham, Zhiheng Li, Yunliang Zhao, Katie Frenis, Caroline Kubaczka, Song Yang, Deepak Jha, Gabriela F Rodrigues-Luiz, R Grant Rowe, Thorsten M Schlaeger, Marcela V Maus, Trista E North, Leonard I Zon, George Q Daley.
      Elucidating mechanisms of T cell development can guide in vitro T cell differentiation from induced pluripotent stem cells (iPSCs) and facilitate off-the-shelf T cell-based immunotherapies. Using a stroma-free human iPSC-T cell differentiation platform, we screened for epigenetic modulators that influence T cell specification and identified the H3K9-directed histone methyltransferases G9a/GLP as repressors of T cell fate. We show that G9a/GLP inhibition during specific time windows of differentiation of hematopoietic stem and progenitor cells (HSPCs) skews cell fates toward lymphoid lineages. Inhibition of G9a/GLP promotes the production of lymphoid cells during zebrafish embryonic hematopoiesis, demonstrating the evolutionary conservation of G9a/GLP function. Importantly, chemical inhibition of G9a/GLP facilitates the generation of mature iPSC-T cells that bear transcriptional similarity to peripheral blood αβ T cells. When engineered to express chimeric antigen receptors, the epigenetically engineered iPSC-T cells exhibit enhanced effector functions in vitro and durable, persistent antitumor activity in a xenograft tumor-rechallenge model.
    Keywords:  CAR-T cells; G9a/GLP; T cell differentiation; cancer immunotherapy; chemical screen; epigenetic regulation; hematopoiesis; lymphoid development; pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.stem.2024.10.004
  8. J Neuroinflammation. 2024 Nov 05. 21(1): 287
    Coenzyme A fueling with pantethine limits autoreactive T cell pathogenicity in experimental neuroinflammation.
    Stefano Angiari, Tommaso Carlucci, Simona L Budui, Simone D Bach, Silvia Dusi, Julia Walter, Elena Ellmeier, Alyssa Schnabl, Anika Stracke, Natalie Bordag, Cansu Tafrali, Rina Demjaha, Michael Khalil, Gabriele Angelini, Eleonora Terrabuio, Enrica C Pietronigro, Elena Zenaro, Carlo Laudanna, Barbara Rossi, Gabriela Constantin.
       BACKGROUND: Immune cell metabolism governs the outcome of immune responses and contributes to the development of autoimmunity by controlling lymphocyte pathogenic potential. In this study, we evaluated the metabolic profile of myelin-specific murine encephalitogenic T cells, to identify novel therapeutic targets for autoimmune neuroinflammation.
    METHODS: We performed metabolomics analysis on actively-proliferating encephalitogenic T cells to study their overall metabolic profile in comparison to resting T cells. Metabolomics, phosphoproteomics, in vitro functional assays, and in vivo studies in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), were then implemented to evaluate the effect of metabolic targeting on autoreactive T cell pathogenicity. Finally, we confirmed the translational potential of our targeting approach in human pro-inflammatory T helper cell subsets and in T cells from MS patients.
    RESULTS: We found that autoreactive encephalitogenic T cells display an altered coenzyme A (CoA) synthesis pathway, compared to resting T cells. CoA fueling with the CoA precursor pantethine (PTTH) affected essential immune-related processes of myelin-specific T cells, such as cell proliferation, cytokine production, and cell adhesion, both in vitro and in vivo. Accordingly, pre-clinical treatment with PTTH before disease onset inhibited the development of EAE by limiting T cell pro-inflammatory potential in vivo. Importantly, PTTH also significantly ameliorated the disease course when administered after disease onset in a therapeutic setting. Finally, PTTH reduced pro-inflammatory cytokine production by human T helper 1 (Th1) and Th17 cells and by T cells from MS patients, confirming its translational potential.
    CONCLUSION: Our data demonstrate that CoA fueling with PTTH in pro-inflammatory and autoreactive T cells may represent a novel therapeutic approach for the treatment of autoimmune neuroinflammation.
    Keywords:  Autoreactive T cells; CoA metabolism; EAE; Immunometabolism; Multiple sclerosis; Pantethine
    DOI:  https://doi.org/10.1186/s12974-024-03270-w
  9. Virology. 2024 Oct 29. pii: S0042-6822(24)00304-0. [Epub ahead of print]600 110280
    MitoTempo treatment as an approach to cure persistent viral infections?
    Jasmin Mischke, Sebastian Klein, Markus Cornberg, Anke R M Kraft.
      Chronic viral infections are characterized by exhausted virus-specific T cells. Exhaustion is associated with mitochondrial dysfunction, revealing a possible target for treatment. Targeting these metabolic processes may interfere with the exhaustion process of immune cells during infection. It has been shown that the mitochondria-targeted antioxidant MitoTempo could restore hepatitis-B-virus-specific T cells in vitro. Thus, we investigated MitoTempo as a treatment option using the chronic lymphocytic choriomeningitis virus (LCMVcl13) mouse model. MitoTempo treatment of chronically LCMVcl13 infected mice resulted in a transient reduction of LCMV titer. However, no obvious restoration of functional LCMV-specific T cells was observed, beside subtle changes in phenotype of GP33- and NP205-specific T cells. However, these changes did not translate into significantly more functional responses. Our study showed a transient antiviral effect of MitoTempo, but no profound effect on exhausted T cell responses, although further studies are needed to further elucidate the mechanism and use of MitoTempo.
    Keywords:  CD8(+) T cells; Chronic viral infection; Immune checkpoint inhibitor therapy; Lymphocytic choriomeningitis virus; MitoTempo; Virus-specific T cells
    DOI:  https://doi.org/10.1016/j.virol.2024.110280
  10. Brain Behav Immun. 2024 Nov 03. pii: S0889-1591(24)00687-1. [Epub ahead of print]
    Acute exercise boosts NAD+ metabolism of human peripheral blood mononuclear cells.
    David Walzik, Niklas Joisten, Alexander Schenk, Sina Trebing, Kirill Schaaf, Alan J Metcalfe, Polyxeni Spiliopoulou, Johanna Hiefner, Adrian McCann, Carsten Watzl, Per Magne Ueland, Sebastian Gehlert, Anna Worthmann, Charles Brenner, Philipp Zimmer.
      Nicotinamide adenine dinucleotide (NAD+) coenzymes are the central electron carriers in biological energy metabolism. Low NAD+ levels are proposed as a hallmark of ageing and several diseases, which has given rise to therapeutic strategies that aim to tackle these conditions by boosting NAD+ levels. As a lifestyle factor with preventive and therapeutic effects, exercise increases NAD+ levels across various tissues, but so far human trials are mostly focused on skeletal muscle. Given that immune cells are mobilized and redistributed in response to acute exercise, we conducted two complementary trials to test the hypothesis that a single exercise session alters NAD+ metabolism of peripheral blood mononuclear cells (PBMCs). In a randomized crossover trial (DRKS00017686) with 24 young adults (12 female) we show that acute exercise increases gene expression and protein abundance of several key NAD+ metabolism enzymes with high conformity between high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). In a longitudinal exercise trial (DRKS00029105) with 12 young adults (6 female) we confirm these results and reveal that - similar to skeletal muscle - NAD+ salvage is pivotal for PBMCs in response to exercise. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD+ salvage pathway, displayed a pronounced increase in gene expression during exercise, which was accompanied by elevated intracellular NAD+ levels and reduced serum levels of the NAD+ precursor nicotinamide. These results demonstrate that acute exercise triggers NAD+ biosynthesis of human PBMCs with potential implications for immunometabolism, immune effector function, and immunological exercise adaptions.
    Keywords:  Exercise; Immune cell; Metabolism; NAD(+); Nicotinamide adenine dinucleotide; PBMC
    DOI:  https://doi.org/10.1016/j.bbi.2024.11.004
  11. Cell Rep. 2024 Nov 05. pii: S2211-1247(24)01264-6. [Epub ahead of print]43(11): 114913
    Metabolite signatures of chronological age, aging, survival, and longevity.
    Paola Sebastiani, Stefano Monti, Michael S Lustgarten, Zeyuan Song, Dylan Ellis, Qu Tian, Michaela Schwaiger-Haber, Ethan Stancliffe, Anastasia Leshchyk, Meghan I Short, Andres V Ardisson Korat, Anastasia Gurinovich, Tanya Karagiannis, Mengze Li, Hannah J Lords, Qingyan Xiang, Megan M Marron, Harold Bae, Mary F Feitosa, Mary K Wojczynski, Jeffrey R O'Connell, May E Montasser, Nicole Schupf, Konstantin Arbeev, Anatoliy Yashin, Nicholas Schork, Kaare Christensen, Stacy L Andersen, Luigi Ferrucci, Noa Rappaport, Thomas T Perls, Gary J Patti.
      Metabolites that mark aging are not fully known. We analyze 408 plasma metabolites in Long Life Family Study participants to characterize markers of age, aging, extreme longevity, and mortality. We identify 308 metabolites associated with age, 258 metabolites that change over time, 230 metabolites associated with extreme longevity, and 152 metabolites associated with mortality risk. We replicate many associations in independent studies. By summarizing the results into 19 signatures, we differentiate between metabolites that may mark aging-associated compensatory mechanisms from metabolites that mark cumulative damage of aging and from metabolites that characterize extreme longevity. We generate and validate a metabolomic clock that predicts biological age. Network analysis of the age-associated metabolites reveals a critical role of essential fatty acids to connect lipids with other metabolic processes. These results characterize many metabolites involved in aging and point to nutrition as a source of intervention for healthy aging therapeutics.
    Keywords:  CP: Metabolism; aging; centenarians; longevity; metabolomics
    DOI:  https://doi.org/10.1016/j.celrep.2024.114913
  12. JCI Insight. 2024 Nov 05. pii: e182328. [Epub ahead of print]
    Flotillin-2 dampens T cell antigen-sensitivity and functionality.
    Sookjin Moon, Fei Zhao, Mohammad N Uddin, Charles J Tucker, Peer Wf Karmaus, Michael B Fessler.
      T cell receptor (TCR) engagement triggers T cell responses, yet how TCR-mediated activation is regulated at the plasma membrane remains unclear. Here, we report that deleting the membrane scaffolding protein Flotillin-2 (Flot2) increases T cell antigen-sensitivity, resulting in enhanced TCR signaling and effector function to weak TCR stimulation. T cell-specific Flot2-deficient mice exhibited reduced tumor growth and enhanced immunity to infection. Flot2-null CD4+ T cells exhibited increased T helper 1 polarization, proliferation, Nur77 induction, and phosphorylation of ZAP70 and ERK1/2 upon weak TCR stimulation, indicating a sensitized TCR-triggering threshold. Single cell-RNA sequencing suggested that Flot2-null CD4+ T cells follow a similar route of activation as wild-type CD4+ T cells but exhibit higher occupancy of a discrete activation state under weak TCR stimulation. Given prior reports that TCR clustering influences sensitivity of T cells to stimuli, we evaluated TCR distribution with super-resolution microscopy. Flot2 ablation increased the number of surface TCR nanoclusters on naïve CD4+ T cells. Collectively, we posit that Flot2 modulates T cell functionality to weak TCR stimulation, at least in part, by regulating surface TCR clustering. Our findings have implications for improving T cell reactivity in diseases with poor antigenicity, such as cancer and chronic infections.
    Keywords:  Immunology; Lipid rafts; T cell receptor; T cells
    DOI:  https://doi.org/10.1172/jci.insight.182328
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