bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–11–17
fourteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism.
  2. Ubiquitination in the T Cell Metabolism-Based Immunotherapy in Diseases.
  3. TET2 regulates early and late transitions in exhausted CD8+ T cell differentiation and limits CAR T cell function.
  4. Epigenetics behind CD8+ T cell activation and exhaustion.
  5. Effect of Nicotinamide Riboside Against the Exhaustion of CD8+ T Cells via Alleviating Mitochondrial Dysfunction.
  6. Age-related loss of intestinal barrier integrity plays an integral role in thymic involution and T cell ageing.
  7. In utero human cytomegalovirus infection expands NK-like FcγRIII+ CD8+ T cells that mediate Fc antibody functions.
  8. Characterization of CD8+ virtual memory T cells in IL-4 knockout mice using single-cell RNA sequencing.
  9. H2S-Prdx4 axis mitigates Golgi stress to bolster tumor-reactive T cell immunotherapeutic response.
  10. Assaying and classifying T cell function by cell morphology.
  11. Semaglutide as a Possible Therapy for Healthy Aging: Targeting the Hallmarks of Aging.
  12. Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance.
  13. Beyond the blood: expanding CAR T cell therapy to solid tumors.
  14. Glisovic-Aplenc T, Diorio C, Chukinas JA, et al. CD38 as a pan-hematologic target for chimeric antigen receptor T cells. Blood Adv. 2023;7(16):4418-4430.
  1. Nat Immunol. 2024 Nov 08.
    Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism.
    Ronal M Peralta, Bingxian Xie, Konstantinos Lontos, Hector Nieves-Rosado, Kellie Spahr, Supriya Joshi, B Rhodes Ford, Kevin Quann, Andrew T Frisch, Victoria Dean, Mary Philbin, Anthony R Cillo, Sebastian Gingras, Amanda C Poholek, Lawrence P Kane, Dayana B Rivadeneira, Greg M Delgoffe.
      CD8+ T cells are critical mediators of antitumor immunity but differentiate into a dysfunctional state, known as T cell exhaustion, after persistent T cell receptor stimulation in the tumor microenvironment (TME). Exhausted T (Tex) cells are characterized by upregulation of coinhibitory molecules and reduced polyfunctionality. T cells in the TME experience an immunosuppressive metabolic environment via reduced levels of nutrients and oxygen and a buildup of lactic acid. Here we show that terminally Tex cells uniquely upregulate Slc16a11, which encodes monocarboxylate transporter 11 (MCT11). Conditional deletion of MCT11 in T cells reduced lactic acid uptake by Tex cells and improved their effector function. Targeting MCT11 with an antibody reduced lactate uptake specifically in Tex cells, which, when used therapeutically in tumor-bearing mice, resulted in reduced tumor growth. These data support a model in which Tex cells upregulate MCT11, rendering them sensitive to lactic acid present at high levels in the TME.
    DOI:  https://doi.org/10.1038/s41590-024-01999-3
  2. Adv Exp Med Biol. 2024 ;1466 19-34
    Ubiquitination in the T Cell Metabolism-Based Immunotherapy in Diseases.
    Ke-Qi Fan, Yi-Yuan Li, Jin Jin.
      Metabolism refers to the exchange of matter and energy between the organism and the environment and the self-renewal process of matter and energy in the organism. Metabolic activities in cells provide them with energy and various substrates required for development. Naive T cells differentiate into effector T cells and memory T cells after activation, and this process is accompanied by reprogramming of metabolism-related gene expression. These metabolic changes reflect physiological changes in different stages of T cell activation and differentiation. An increasing number of studies have shown that many autoimmune diseases and organ transplantation are accompanied by disorders and imbalances in T cell metabolism. To treat these diseases, related drugs can be used to regulate T cell activation, differentiation, and function. Therefore, T cell metabolism can serve as a new potential target for regulating immune responses.
    Keywords:  Immunotherapy; Metabolism; T cells; Ubiquitination
    DOI:  https://doi.org/10.1007/978-981-97-7288-9_2
  3. Sci Adv. 2024 Nov 15. 10(46): eadp9371
    TET2 regulates early and late transitions in exhausted CD8+ T cell differentiation and limits CAR T cell function.
    Alexander J Dimitri, Amy E Baxter, Gregory M Chen, Caitlin R Hopkins, Geoffrey T Rouin, Hua Huang, Weimin Kong, Christopher H Holliday, Volker Wiebking, Robert Bartoszek, Sydney Drury, Katherine Dalton, Owen M Koucky, Zeyu Chen, Josephine R Giles, Alexander T Dils, In-Young Jung, Roddy O'Connor, Sierra Collins, John K Everett, Kevin Amses, Scott Sherrill-Mix, Aditi Chandra, Naomi Goldman, Golnaz Vahedi, Julie K Jadlowsky, Regina M Young, Jan Joseph Melenhorst, Shannon L Maude, Bruce L Levine, Noelle V Frey, Shelley L Berger, Stephan A Grupp, David L Porter, Friederike Herbst, Matthew H Porteus, Shannon A Carty, Frederic D Bushman, Evan W Weber, E John Wherry, Martha S Jordan, Joseph A Fraietta.
      CD8+ T cell exhaustion hampers control of cancer and chronic infections and limits chimeric antigen receptor (CAR) T cell efficacy. Targeting TET2 in CAR T cells provides therapeutic benefit; however, TET2's role in exhausted T cell (TEX) development is unclear. In chronic lymphocytic choriomeningitis virus (LCMV) infection, TET2 drove conversion from stem cell-like TEX progenitors toward terminally differentiated and effector (TEFF)-like TEX. TET2 also enforced a terminally differentiated state in the early bifurcation between TEFF and TEX, indicating broad roles for TET2 in acquisition of effector biology. To exploit the therapeutic potential of TET2, we developed clinically actionable TET2-targeted CAR T cells by disrupting TET2 via knock-in of a safety switch alongside CAR knock-in at the TRAC locus. TET2-targeted CAR T cells exhibited restrained terminal exhaustion in vitro and enhanced antitumor responses in vivo. Thus, TET2 regulates fate transitions in TEX differentiation and can be targeted with a safety mechanism in CAR T cells for improved tumor control.
    DOI:  https://doi.org/10.1126/sciadv.adp9371
  4. Genes Immun. 2024 Nov 14.
    Epigenetics behind CD8+ T cell activation and exhaustion.
    Hao Zu, Xiaoqin Chen.
      CD8+ T cells play a critical role in specific immunity. In recent years, cell therapy has been emerging rapidly. The specific cytotoxic capabilities of these cells enable them to precisely identify and kill cells presenting specific antigens. This has demonstrated promise in the treatment of autoimmune diseases and cancers, with wide-ranging applications and value. However, in some diseases, such as tumors and chronic infections, T cells may adopt an exhausted phenotype, resulting in a loss of cytotoxicity and limiting their further application. Epigenetics plays a significant role in the differentiation and regulation of gene expression in cells. There is extensive evidence indicating that epigenetic remodeling plays an important role in T cell exhaustion. Therefore, further understanding its role in CD8+ T cell function can provide insights into the programmatic regulation of CD8+ T cells from a genetic perspective and overcome these diseases. We attempted to describe the relationship between the activation, function, and exhaustion mechanisms of CD8+ T cells, as well as epigenetics. This understanding makes it possible for us to address the aforementioned issues.
    DOI:  https://doi.org/10.1038/s41435-024-00307-1
  5. Nutrients. 2024 Oct 22. pii: 3577. [Epub ahead of print]16(21):
    Effect of Nicotinamide Riboside Against the Exhaustion of CD8+ T Cells via Alleviating Mitochondrial Dysfunction.
    Ying Xiao, Nengzhi Pang, Sixi Ma, Mengqi Gao, Lili Yang.
      Background: Targeting mitochondria and protecting the mitochondrial function of CD8+ T cells are crucial for enhancing the clinical efficacy of cancer immunotherapy. Objectives: In this study, our objective was to investigate the potential of nicotinamide riboside (NR) in preserving the mitochondrial function of CD8+ T cells and mitigating their exhaustion. Methods: We established two in vitro models to induce CD8+ T cell exhaustion either by tumor cell-conditioned medium (TCM) or by continuous stimulation with OVA(257-264) peptide. CD8+ T cells were treated in the absence/presence of NR. Results: Our findings demonstrated that NR supplementation effectively inhibited CD8+ T cell exhaustion and preserved mitochondrial function in both models. Moreover, apoptosis of CD8+ T cells was reduced after NR treatment. Western blot data indicated that NR treatment upregulated Silent information regulator 1 (SirT1) expression. Further inhibition of Sirt1 activity using EX527 uncovered that the inhibitory effect of NR on CD8+ T cell exhaustion and its protective effect on mitochondria were attenuated. Conclusions: In conclusion, our results indicate that NR supplementation attenuates CD8+ T cell exhaustion, and its underlying mechanism is associated with increased mitochondrial function regulated by the SirT1 pathway. Our research provides evidence that NR may assist in enhancing the clinical efficacy of immunotherapy.
    Keywords:  CD8+ T cells exhaustion; mitochondrial; nicotinamide ribose
    DOI:  https://doi.org/10.3390/nu16213577
  6. Aging Cell. 2024 Nov 15. e14401
    Age-related loss of intestinal barrier integrity plays an integral role in thymic involution and T cell ageing.
    Jessica Conway, Erica N De Jong, Andrea J White, Ben Dugan, Nia Paddison Rees, Sonia M Parnell, Lisa E Lamberte, Archana Sharma-Oates, Jack Sullivan, Claudio Mauro, Willem van Schaik, Graham Anderson, Dawn M E Bowdish, Niharika A Duggal.
      The intestinal epithelium serves as a physical and functional barrier against harmful substances, preventing their entry into the circulation and subsequent induction of a systemic immune response. Gut barrier dysfunction has recently emerged as a feature of ageing linked to declining health, and increased intestinal membrane permeability has been shown to promote heightened systemic inflammation in aged hosts. Concurrent with age-related changes in the gut microbiome, the thymic microenvironment undergoes a series of morphological, phenotypical and architectural alterations with age, including disorganisation of the corticomedullary junction, increased fibrosis, increased thymic adiposity and the accumulation of senescent cells. However, a direct link between gut barrier dysbiosis and thymic involution leading to features of immune ageing has not been explored thus far. Herein, we reveal strong associations between enhanced microbial translocation and the peripheral accumulation of terminally differentiated, senescent and exhausted T cells and the compensatory expansion of regulatory T cells in older adults. Crucially, we demonstrate that aged germ-free mice are protected from age-related increases in intestinal permeability, highlighting the direct impact of mucosal permeability on thymic ageing. Together, these findings establish a novel mechanism by which gut barrier dysfunction drives systemic activation of the immune system during ageing through thymic involution. This enhances our understanding of drivers of T cell ageing and opens up the possibility for the use of microbiome-based interventions to restore immune homeostasis and promote healthy ageing in older adults.
    Keywords:  T cell ageing; immunesenescence; intestinal barrier leakage; thymic involution
    DOI:  https://doi.org/10.1111/acel.14401
  7. J Clin Invest. 2024 Nov 12. pii: e181342. [Epub ahead of print]
    In utero human cytomegalovirus infection expands NK-like FcγRIII+ CD8+ T cells that mediate Fc antibody functions.
    Eleanor C Semmes, Danielle R Nettere, Ashley N Nelson, Jillian H Hurst, Derek W Cain, Trevor D Burt, Joanne Kurtzberg, R Keith Reeves, Carolyn B Coyne, Genevieve G Fouda, Justin Pollara, Sallie R Permar, Kyle M Walsh.
      Human cytomegalovirus (HCMV) profoundly impacts host T and natural killer (NK) cells across the lifespan, yet how this common congenital infection modulates developing fetal immune cell compartments remains underexplored. Using cord blood from neonates with and without congenital HCMV (cCMV) infection, we identify an expansion of Fcγ receptor III (FcγRIII)-expressing CD8+ T cells following HCMV exposure in utero. Most FcγRIII+ CD8+ T cells express the canonical αβ T cell receptor (TCR) but a proportion express non-canonical γδ TCR. FcγRIII+ CD8+ T cells are highly differentiated and have increased expression of NK cell markers and cytolytic molecules. Transcriptional analysis reveals FcγRIII+ CD8+ T cells upregulate T-bet and downregulate BCL11B, known transcription factors that govern T/NK cell fate. We show that FcγRIII+ CD8+ T cells mediate antibody-dependent IFNγ production and degranulation against IgG-opsonized target cells, similar to NK cell antibody-dependent cellular cytotoxicity (ADCC). FcγRIII+ CD8+ T cell Fc effector functions were further enhanced by interleukin-15 (IL-15), as has been observed in neonatal NK cells. Our study reveals that FcγRIII+ CD8+ T cells elicited in utero by HCMV infection can execute Fc-mediated effector functions bridging cellular and humoral immunity and may be a promising target for antibody-based therapeutics and vaccination in early life.
    Keywords:  Immunoglobulins; Immunology; Infectious disease; NK cells; T cells
    DOI:  https://doi.org/10.1172/JCI181342
  8. Biochem Biophys Res Commun. 2024 Nov 04. pii: S0006-291X(24)01486-4. [Epub ahead of print]738 150950
    Characterization of CD8+ virtual memory T cells in IL-4 knockout mice using single-cell RNA sequencing.
    Sung Min Choi, Hi Jung Park, Hyun Ji Boo, Kyeong Cheon Jung, Jae Il Lee.
      Antigen-inexperienced memory-phenotype CD8+ T cells are categorized as innate memory cells in the thymus or virtual memory (VM) CD8+ T cells in peripheral tissues. The key distinction between these cell types is their differing responses to IL-4, but the minimal effect of IL-4 on VM CD8+ T cell expansion in the periphery is not well understood. To address this, we investigated the development of VM CD8+ T cells in the periphery of IL-4 knockout (KO) C57BL/6 mouse. CD8+ splenocytes were isolated from the spleen of wilt-type (WT) and IL-4 KO mice, followed by single-cell RNA sequencing and Seurat analysis on sorted CD8+ cells using the 10x Genomics platform. This study identified various CD8+ T cell subtypes, including naïve, effector, IFN-stimulated, true memory (TM), and VM T cells. VM CD8+ T cells were characterized by high expression of Cd44, Cxcr3, Il2rb, Eomes, Tbx21, Ly6c2, and low expression of Itga4. In IL-4-deficient mouse, macrophages were significantly reduced, while memory T cell populations showed a slight increase compared to WT mouse. Both Itga4+ TM and Itga4- VM CD8+ T cells were more abundant in IL-4 KO mouse. Within the VM T cell group, Ly6a- VM CD8+ T cells were reduced, while Ly6a + VM CD8+ T cells were increased relative to WT mouse. These Ly6a+ VM CD8+ cells exhibited high expression of genes linked to type I IFN signaling, such as Isg15, Ifit1, and Stat1. Our findings suggest that IFN-influenced Ly6a + VM CD8+ T cells play a role in maintaining the peripheral VM CD8+ T cell population in the absence of IL-4.
    Keywords:  CD8 T cell; Interleukin-4; Ly6a; Single-cell RNA sequencing; Virtual memory
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150950
  9. Sci Adv. 2024 Nov 15. 10(46): eadp1152
    H2S-Prdx4 axis mitigates Golgi stress to bolster tumor-reactive T cell immunotherapeutic response.
    Nathaniel Oberholtzer, Paramita Chakraborty, Mohamed Faisal Kassir, James Dressman, Satyajit Das, Stephanie Mills, Susana Comte-Walters, Monika Gooz, Seungho Choi, Rasesh Y Parikh, Zacharia Hedley, Silvia Vaena, Reid DeMass, Gina Scurti, Martin Romeo, Vamsi K Gangaraju, Stefano Berto, Elizabeth Hill, Lauren E Ball, Anand S Mehta, Eduardo N Maldonado, Michael I Nishimura, Besim Ogretmen, Shikhar Mehrotra.
      The role of tumor microenvironment (TME)-associated inadequate protein modification and trafficking due to insufficiency in Golgi function, leading to Golgi stress, in the regulation of T cell function is largely unknown. Here, we show that disruption of Golgi architecture under TME stress, identified by the decreased expression of GM130, was reverted upon treatment with hydrogen sulfide (H2S) donor GYY4137 or overexpressing cystathionine β-synthase (CBS), an enzyme involved in the biosynthesis of endogenous H2S, which also promoted stemness, antioxidant capacity, and increased protein translation, mediated in part by endoplasmic reticulum-Golgi shuttling of Peroxiredoxin-4. In in vivo models of melanoma and lymphoma, antitumor T cells conditioned ex vivo with exogenous H2S or overexpressing CBS demonstrated superior tumor control upon adoptive transfer. Further, T cells with high Golgi content exhibited unique metabolic and glycation signatures with enhanced antitumor capacity. These data suggest that strategies to mitigate Golgi network stress or using Golgihi tumor-reactive T cells can improve tumor control upon adoptive transfer.
    DOI:  https://doi.org/10.1126/sciadv.adp1152
  10. BioMedInformatics. 2024 Jun;4(2): 1144-1154
    Assaying and classifying T cell function by cell morphology.
    Xin Wang, Stacey M Fernandes, Jennifer R Brown, Lance C Kam.
      Immune cell function varies tremendously between individuals, posing a major challenge to emerging cellular immunotherapies. This report pursues the use of cell morphology as an indicator of high-level T cell function. Short-term spreading of T cells on planar, elastic surfaces was quantified by 11 morphological parameters and analyzed to identify effects of both intrinsic and extrinsic factors. Our findings identified morphological features that varied between T cells isolated from healthy donors and those from patients being treated for Chronic Lymphocytic Leukemia (CLL). This approach also identified differences between cell responses to substrates of different elastic modulus. Combining multiple features through a machine learning approach such as Decision Tree or Random Forest provided an effective means for identifying whether T cells came from healthy or CLL donors. Further development of this approach could lead to a rapid assay of T cell function to guide cellular immunotherapy.
    Keywords:  CLL; T cell mechanosensing; T cell morphology; immunotherapy; intrinsic state; machine learning; primary human T cells; rapid measurement; surrounding environment
    DOI:  https://doi.org/10.3390/biomedinformatics4020063
  11. Ageing Res Rev. 2024 Nov 13. pii: S1568-1637(24)00400-8. [Epub ahead of print] 102582
    Semaglutide as a Possible Therapy for Healthy Aging: Targeting the Hallmarks of Aging.
    Gabriela Ueta Ortiz, Ellen Cristini de Freitas.
      With an aging population, the investigation of therapies that promote healthy aging becomes increasingly urgent. Here we discuss how Semaglutide can be a potential therapy to contribute to this goal by targeting key hallmarks of aging, such as inflammation, oxidative stress and stem cell exhaustion.
    Keywords:  healthy aging; inflammation; oxidative stress; semaglutide; stem cell exhaustion
    DOI:  https://doi.org/10.1016/j.arr.2024.102582
  12. Cancer Cell. 2024 Nov 01. pii: S1535-6108(24)00398-2. [Epub ahead of print]
    Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance.
    Heng Lin, Kole Tison, Yuheng Du, Paul Kirchhoff, Chan Kim, Weichao Wang, Hannah Yang, Michael Pitter, Jiali Yu, Peng Liao, Jiajia Zhou, Linda Vatan, Sara Grove, Shuang Wei, Thomas Vigil, Yatrik M Shah, Richard Mortensen, Ilona Kryczek, Lana Garmire, Jwala P Sivaccumar, Ashwin Kumar Ramesh, Ningyan Zhang, Zhiqiang An, Shaomeng Wang, Weiping Zou.
      Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discover SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identify a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitize tumors to ferroptosis, curb tumor progression, and bolster ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target for treating SLC13A3+ cancer.
    Keywords:  NRF2; SLC13A3; SLC13A3 inhibitor; SLC7A11; T cell immunity; ferroptosis; immune checkpoint blockade; itaconate; macrophages; tumor
    DOI:  https://doi.org/10.1016/j.ccell.2024.10.010
  13. Nat Biotechnol. 2024 Nov 12.
    Beyond the blood: expanding CAR T cell therapy to solid tumors.
    Ugur Uslu, Carl H June.
      Chimeric antigen receptor (CAR) T cell therapy stands as a transformative advancement in immunotherapy, triumphing against hematological malignancies and, increasingly, autoimmune disorders. After a decade of relatively modest results for solid tumors, recent clinical trials and patient reports have also started to yield promising outcomes in glioblastoma and other challenging solid tumor entities. This Perspective seeks to explore the reasons behind these latest achievements and discusses how they can be sustained and expanded through different strategies involving CAR engineering and synthetic biology. Furthermore, we critically analyze how these breakthroughs can be leveraged to maintain momentum and broaden the therapeutic impact of CAR T cells across a variety of solid tumor landscapes.
    DOI:  https://doi.org/10.1038/s41587-024-02446-2
  14. Blood Adv. 2024 Nov 26. 8(22): 5789
    Glisovic-Aplenc T, Diorio C, Chukinas JA, et al. CD38 as a pan-hematologic target for chimeric antigen receptor T cells. Blood Adv. 2023;7(16):4418-4430.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2024014719
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