bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–08–06
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Ketolysis drives CD8+ T cell effector function through effects on histone acetylation.
  2. Enolase represents a metabolic checkpoint controlling the differential exhaustion programmes of hepatitis virus-specific CD8+ T cells.
  3. Extracellular vesicles in COVID-19 convalescence can regulate T cell metabolism and function.
  4. Ncoa2 promotes CD8+ T cell-mediated anti-tumor immunity by stimulating T-cell activation via upregulation of PGC-1α critical for mitochondrial function.
  5. The pseudokinase Trib1 regulates the transition of exhausted T cells to a KLR+ CD8+ effector state, and its deletion improves checkpoint blockade.
  6. A data-driven Boolean model explains memory subsets and evolution in CD8+ T cell exhaustion.
  7. Hallmarks of CD8+ T cell dysfunction are established within hours of tumor antigen encounter before cell division.
  8. Vaccine adjuvant-elicited CD8+ T cell immunity is co-dependent on T-bet and FOXO1.
  9. Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton.
  10. Environmental Enrichment Improves Motor Function and Muscle Transcriptome of Aged Mice.
  1. Immunity. 2023 Jul 20. pii: S1074-7613(23)00314-X. [Epub ahead of print]
    Ketolysis drives CD8+ T cell effector function through effects on histone acetylation.
    Katarzyna M Luda, Joseph Longo, Susan M Kitchen-Goosen, Lauren R Duimstra, Eric H Ma, McLane J Watson, Brandon M Oswald, Zhen Fu, Zachary Madaj, Ariana Kupai, Bradley M Dickson, Lisa M DeCamp, Michael S Dahabieh, Shelby E Compton, Robert Teis, Irem Kaymak, Kin H Lau, Daniel P Kelly, Patrycja Puchalska, Kelsey S Williams, Connie M Krawczyk, Dominique Lévesque, François-Michel Boisvert, Ryan D Sheldon, Scott B Rothbart, Peter A Crawford, Russell G Jones.
      Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)-as essential fuels supporting CD8+ T cell metabolism and effector function. βOHB directly increased CD8+ T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8+ Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8+ T cell function. Mechanistically, βOHB was a major substrate for acetyl-CoA production in CD8+ T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses.
    Keywords:  CD8(+) T cells; TCA cycle; acetyl-CoA; cancer immunology; effector function; epigenetics; ketolysis; ketone bodies; metabolism
    DOI:  https://doi.org/10.1016/j.immuni.2023.07.002
  2. Gut. 2023 Aug 04. pii: gutjnl-2022-328734. [Epub ahead of print]
    Enolase represents a metabolic checkpoint controlling the differential exhaustion programmes of hepatitis virus-specific CD8+ T cells.
    Frances Winkler, Anna V Hipp, Carlos Ramirez, Bianca Martin, Matteo Villa, Emilia Neuwirt, Oliver Gorka, Jeroen Aerssens, Susanne E Johansson, Nisha Rana, Sian Llewellyn-Lacey, David A Price, Marcus Panning, Olaf Groß, Erika L Pearce, Carl M Hermann, Kathrin Schumann, Luciana Hannibal, Christoph Neumann-Haefelin, Tobias Boettler, Percy Knolle, Maike Hofmann, Dirk Wohlleber, Robert Thimme, Bertram Bengsch.
       OBJECTIVE: Exhausted T cells with limited effector function are enriched in chronic hepatitis B and C virus (HBV and HCV) infection. Metabolic regulation contributes to exhaustion, but it remains unclear how metabolism relates to different exhaustion states, is impacted by antiviral therapy, and if metabolic checkpoints regulate dysfunction.
    DESIGN: Metabolic state, exhaustion and transcriptome of virus-specific CD8+ T cells from chronic HBV-infected (n=31) and HCV-infected patients (n=52) were determined ex vivo and during direct-acting antiviral (DAA) therapy. Metabolic flux and metabolic checkpoints were tested in vitro. Intrahepatic virus-specific CD8+ T cells were analysed by scRNA-Seq in a HBV-replicating murine in vivo model of acute and chronic infection.
    RESULTS: HBV-specific (core18-27, polymerase455-463) and HCV-specific (NS31073-1081, NS31406-1415, NS5B2594-2602) CD8+ T cell responses exhibit heterogeneous metabolic profiles connected to their exhaustion states. The metabolic state was connected to the exhaustion profile rather than the aetiology of infection. Mitochondrial impairment despite intact glucose uptake was prominent in severely exhausted T cells linked to elevated liver inflammation in chronic HCV infection and in HBV polymerase455-463 -specific CD8+ T cell responses. In contrast, relative metabolic fitness was observed in HBeAg-negative HBV infection in HBV core18-27-specific responses. DAA therapy partially improved mitochondrial programmes in severely exhausted HCV-specific T cells and enriched metabolically fit precursors. We identified enolase as a metabolic checkpoint in exhausted T cells. Metabolic bypassing improved glycolysis and T cell effector function. Similarly, enolase deficiency was observed in intrahepatic HBV-specific CD8+ T cells in a murine model of chronic infection.
    CONCLUSION: Metabolism of HBV-specific and HCV-specific T cells is strongly connected to their exhaustion severity. Our results highlight enolase as metabolic regulator of severely exhausted T cells. They connect differential bioenergetic fitness with distinct exhaustion subtypes and varying liver disease, with implications for therapeutic strategies.
    Keywords:  alpha beta T cells; chronic viral hepatitis; hepatitis B; hepatitis C; immunology in hepatology
    DOI:  https://doi.org/10.1136/gutjnl-2022-328734
  3. iScience. 2023 Aug 18. 26(8): 107280
    Extracellular vesicles in COVID-19 convalescence can regulate T cell metabolism and function.
    Molly S George, Jenifer Sanchez, Christina Rollings, David Fear, Peter Irving, Linda V Sinclair, Anna Schurich.
      Long-term T cell dysregulation has been reported following COVID-19 disease. Prolonged T cell activation is associated with disease severity and may be implicated in producing long-covid symptoms. Here, we assess the role of extracellular vesicles (EV) in regulating T cell function over several weeks post COVID-19 disease. We find that alterations in cellular origin and protein content of EV in COVID-19 convalescence are linked to initial disease severity. We demonstrate that convalescent donor-derived EV can alter the function and metabolic rewiring of CD4 and CD8 T cells. Of note, EV following mild, but not severe disease, show distinctly immune-suppressive properties, reducing T cell effector cytokine production and glucose metabolism. Mechanistically our data indicate the involvement of EV-surface ICAM-1 in facilitating EV-T cell interaction. Our data demonstrate that circulatory EV are phenotypically and functionally altered several weeks following acute infection, suggesting a role for EV as long-term immune modulators.
    Keywords:  Immunology; Virology
    DOI:  https://doi.org/10.1016/j.isci.2023.107280
  4. Cancer Immunol Res. 2023 Aug 04. pii: CIR-23-0092. [Epub ahead of print]
    Ncoa2 promotes CD8+ T cell-mediated anti-tumor immunity by stimulating T-cell activation via upregulation of PGC-1α critical for mitochondrial function.
    Xiancai Zhong, Hongmin Wu, Ching Ouyang, Wencan Zhang, Yun Shi, Yi-Chang Wang, David K Ann, Yousang Gwack, Weirong Shang, Zuoming Sun.
      Nuclear receptor coactivator 2 (Ncoa2) is a member of the Ncoa family of co-activators, and we previously showed that Ncoa2 regulates the differentiation of induced regulatory T cells. However, it remains unknown if Ncoa2 plays a role in CD8+ T-cell function. Here, we show that Ncoa2 promotes CD8+ T cell-mediated immune responses against tumors by stimulating T-cell activation via upregulating PGC-1α expression to enhance mitochondrial function. Mice deficient in Ncoa2 in T cells (Ncoa2fl/fl/CD4Cre) displayed defective immune responses against implanted MC38 tumors, which associated with significantly reduced tumor-infiltrating CD8+ T cells and decreased IFNγ production. Consistently, CD8+ T cells from Ncoa2fl/fl/CD4Cre mice failed to reject tumors after adoptive transfer into Rag1-/- mice. Further, in response to TCR stimulation, Ncoa2fl/fl/CD4Cre CD8+ T cells failed to increase mitochondrial mass, showed impaired oxidative phosphorylation, and had lower expression of PGC-1α, a master regulator of mitochondrial biogenesis and function. Mechanically, T cell activation-induced phosphorylation of CREB triggered the recruitment of Ncoa2 to bind to enhancers, thus, stimulating PGC-1α expression. Forced expression of PGC-1α in Ncoa2fl/fl/CD4Cre CD8+ T cells restored mitochondrial function, T-cell activation, IFNγ production, and anti-tumor immunity. This work informs the development of Ncoa2-based therapies that modulate CD8+ T cell-mediated anti-tumor immune responses.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0092
  5. Cell Rep. 2023 Jul 31. pii: S2211-1247(23)00916-6. [Epub ahead of print]42(8): 112905
    The pseudokinase Trib1 regulates the transition of exhausted T cells to a KLR+ CD8+ effector state, and its deletion improves checkpoint blockade.
    Susan E McClory, Oishi Bardhan, Kelly S Rome, Josephine R Giles, Amy E Baxter, Lanwei Xu, Phyllis A Gimotty, Robert B Faryabi, E John Wherry, Warren S Pear, Martha S Jordan.
      CD8+ T cell exhaustion (TEX) impairs the ability of T cells to clear chronic infection or cancer. While TEX are hypofunctional, some TEX retain effector gene signatures, a feature associated with killer lectin-like receptor (KLR) expression. Although KLR+ TEX (TKLR) may improve control of chronic antigen, the signaling molecules regulating this population are poorly understood. Using single-cell RNA sequencing (scRNA-seq), flow cytometry, RNA velocity, and single-cell T cell receptor sequencing (scTCR-seq), we demonstrate that deleting the pseudokinase Trib1 shifts TEX toward CX3CR1+ intermediates with robust enrichment of TKLR via clonal T cell expansion. Adoptive transfer studies demonstrate this shift toward CD8+ TKLR in Trib1-deficient cells is CD8 intrinsic, while CD4-depletion studies demonstrate CD4+ T cells are required for improved viral control in Trib1 conditional knockout mice. Further, Trib1 loss augments anti-programmed death-ligand 1 (PD-L1) blockade to improve viral clearance. These data identify Trib1 as an important regulator of CD8+ TEX whose targeting enhances the TKLR effector state and improves checkpoint inhibitor therapy.
    Keywords:  CD8 T cell exhaustion; CP: Immunology; Immune checkpoint blockade; LCMV clone 13; PD-L1; Tribbles; immnotherapy
    DOI:  https://doi.org/10.1016/j.celrep.2023.112905
  6. NPJ Syst Biol Appl. 2023 07 31. 9(1): 36
    A data-driven Boolean model explains memory subsets and evolution in CD8+ T cell exhaustion.
    Geena V Ildefonso, Stacey D Finley.
      T cells play a key role in a variety of immune responses, including infection and cancer. Upon stimulation, naïve CD8+ T cells proliferate and differentiate into a variety of memory and effector cell types; however, failure to clear antigens causes prolonged stimulation of CD8+ T cells, ultimately leading to T cell exhaustion (TCE). The functional and phenotypic changes that occur during CD8+ T cell differentiation are well characterized, but the underlying gene expression state changes are not completely understood. Here, we utilize a previously published data-driven Boolean model of gene regulatory interactions shown to mediate TCE. Our network analysis and modeling reveal the final gene expression states that correspond to TCE, along with the sequence of gene expression patterns that give rise to those final states. With a model that predicts the changes in gene expression that lead to TCE, we could evaluate strategies to inhibit the exhausted state. Overall, we demonstrate that a common pathway model of CD8+ T cell gene regulatory interactions can provide insights into the transcriptional changes underlying the evolution of cell states in TCE.
    DOI:  https://doi.org/10.1038/s41540-023-00297-2
  7. Nat Immunol. 2023 Aug 03.
    Hallmarks of CD8+ T cell dysfunction are established within hours of tumor antigen encounter before cell division.
    Michael W Rudloff, Paul Zumbo, Natalie R Favret, Jessica J Roetman, Carlos R Detrés Román, Megan M Erwin, Kristen A Murray, Sriya T Jonnakuti, Friederike Dündar, Doron Betel, Mary Philip.
      Tumor-specific CD8+ T cells (TST) in patients with cancer are dysfunctional and unable to halt cancer progression. TST dysfunction, also known as exhaustion, is thought to be driven by chronic T cell antigen receptor (TCR) stimulation over days to weeks. However, we know little about the interplay between CD8+ T cell function, cell division and epigenetic remodeling within hours of activation. Here, we assessed early CD8+ T cell differentiation, cell division, chromatin accessibility and transcription in tumor-bearing mice and acutely infected mice. Surprisingly, despite robust activation and proliferation, TST had near complete effector function impairment even before undergoing cell division and had acquired hallmark chromatin accessibility features previously associated with later dysfunction/exhaustion. Moreover, continued tumor/antigen exposure drove progressive epigenetic remodeling, 'imprinting' the dysfunctional state. Our study reveals the rapid divergence of T cell fate choice before cell division in the context of tumors versus infection.
    DOI:  https://doi.org/10.1038/s41590-023-01578-y
  8. Cell Rep. 2023 Jul 28. pii: S2211-1247(23)00922-1. [Epub ahead of print]42(8): 112911
    Vaccine adjuvant-elicited CD8+ T cell immunity is co-dependent on T-bet and FOXO1.
    Daria L Ivanova, Scott B Thompson, Jared Klarquist, Michael G Harbell, Augustus M Kilgore, Erika L Lasda, Jay R Hesselberth, Christopher A Hunter, Ross M Kedl.
      T-bet and FOXO1 are transcription factors canonically associated with effector and memory T cell fates, respectively. During an infectious response, these factors direct the development of CD8+ T cell fates, where T-bet deficiency leads to ablation of only short-lived effector cells, while FOXO1 deficiency results in selective loss of memory. In contrast, following adjuvanted subunit vaccination in mice, both effector- and memory-fated T cells are compromised in the absence of either T-bet or FOXO1. Thus, unlike responses to challenge with Listeria monocytogenes, productive CD8+ T cell responses to adjuvanted vaccination require coordinated regulation of FOXO1 and T-bet transcriptional programs. Single-cell RNA sequencing analysis confirms simultaneous T-bet, FOXO1, and TCF1 transcriptional activity in vaccine-elicited, but not infection-elicited, T cells undergoing clonal expansion. Collectively, our data show that subunit vaccine adjuvants elicit T cell responses dependent on transcription factors associated with effector and memory cell fates.
    Keywords:  CD8; CP: Immunology; FOXO1; T cell; T-bet; adjuvant; transcription factor; vaccine
    DOI:  https://doi.org/10.1016/j.celrep.2023.112911
  9. Nat Commun. 2023 07 31. 14(1): 4587
    Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton.
    Madison L Doolittle, Dominik Saul, Japneet Kaur, Jennifer L Rowsey, Stephanie J Vos, Kevin D Pavelko, Joshua N Farr, David G Monroe, Sundeep Khosla.
      Senescence drives organismal aging, yet the deep characterization of senescent cells in vivo remains incomplete. Here, we apply mass cytometry by time-of-flight using carefully validated antibodies to analyze senescent cells at single-cell resolution. We use multiple criteria to identify senescent mesenchymal cells that are growth-arrested and resistant to apoptosis. These p16 + Ki67-BCL-2+ cells are highly enriched for senescence-associated secretory phenotype and DNA damage markers, are strongly associated with age, and their percentages are increased in late osteoblasts/osteocytes and CD24high osteolineage cells. Moreover, both late osteoblasts/osteocytes and CD24high osteolineage cells are robustly cleared by genetic and pharmacologic senolytic therapies in aged mice. Following isolation, CD24+ skeletal cells exhibit growth arrest, senescence-associated β-galactosidase positivity, and impaired osteogenesis in vitro. These studies thus provide an approach using multiplexed protein profiling to define senescent mesenchymal cells in vivo and identify specific skeletal cell populations cleared by senolytics.
    DOI:  https://doi.org/10.1038/s41467-023-40393-9
  10. Adv Biol (Weinh). 2023 Jul 30. e2300148
    Environmental Enrichment Improves Motor Function and Muscle Transcriptome of Aged Mice.
    Wei Huang, Rhiannon Bates, Xunchang Zou, Nicholas J Queen, Xiaokui Mo, W David Arnold, Alissa Ray, Gregory Owendoff, Lei Cao.
      Aging results in the progressive decline of muscle strength. Interventions to maintain muscle strength may mitigate the age-related loss of physical function, thus maximizing health span. The work on environmental enrichment (EE), an experimental paradigm recapitulating aspects of an active lifestyle, has revealed EE-induced metabolic benefits mediated by a brain-fat axis across the lifespan of mice. EE initiated at 18-month of age shows a trend toward an increased mean lifespan. While previous work described EE's influences on the aging dynamics of several central-peripheral processes, its influence on muscle remained understudied. Here, the impact of EE is investigated on motor function, neuromuscular physiology, and the skeletal muscle transcriptome. EE is initiated in 20-month-old mice for a five-month period. EE mice exhibit greater relative lean mass that is associated with improved mobility and hindlimb grip strength. Transcriptomic profiling of muscle tissue reveals an EE-associated enrichment of gene expression within several metabolic pathways related to oxidative phosphorylation and the TCA cycle. Many mitochondrial-related genes-several of which participate in the electron transport chain-are upregulated. Stress-responsive signaling pathways are downregulated because of EE. The results suggest that EE improves motor function-possibly through preservation of mitochondrial function-even late in life.
    Keywords:  aged mice; environment enrichment; mitochondrial genes; motor function; muscle transcriptomics; neuromuscular physiology
    DOI:  https://doi.org/10.1002/adbi.202300148
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