bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022–12–25
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Rebalancing TGFβ1/BMP signals in exhausted T cells unlocks responsiveness to immune checkpoint blockade therapy.
  2. Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity.
  3. TCF-1 regulates NKG2D expression on CD8 T cells during anti-tumor responses.
  4. Implication of IL-7 receptor alpha chain expression by CD8+ T cells and its signature in defining biomarkers in aging.
  5. Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer.
  6. Markers of immune dysregulation in response to the ageing gut: insights from aged murine gut microbiota transplants.
  7. Acly Deficiency Enhances Myelopoiesis through Acetyl Coenzyme A and Metabolic-Epigenetic Cross-Talk.
  8. Regulation of Mitochondrial Energy Metabolism by Glutaredoxin 5 in the Apicomplexan Parasite Neospora caninum.
  9. NRF2/Itaconate Axis Regulates Metabolism and Inflammatory Properties of T Cells in Children with JIA.
  10. T Cell Transcriptional Signatures of Influenza A/H3N2 Antibody Response to High Dose Influenza and Adjuvanted Influenza Vaccine in Older Adults.
  1. Nat Immunol. 2022 Dec 21.
    Rebalancing TGFβ1/BMP signals in exhausted T cells unlocks responsiveness to immune checkpoint blockade therapy.
    Abbey A Saadey, Amir Yousif, Nicole Osborne, Roya Shahinfar, Yu-Lin Chen, Brooke Laster, Meera Rajeev, Parker Bauman, Amy Webb, Hazem E Ghoneim.
      T cell dysfunctionality prevents the clearance of chronic infections and cancer. Furthermore, epigenetic programming in dysfunctional CD8+ T cells limits their response to immunotherapies, including immune checkpoint blockade (ICB). However, it is unclear which upstream signals drive acquisition of dysfunctional epigenetic programs, and whether therapeutically targeting these signals can remodel terminally dysfunctional T cells to an ICB-responsive state. Here we innovate an in vitro model system of stable human T cell dysfunction and show that chronic TGFβ1 signaling in posteffector CD8+ T cells accelerates their terminal dysfunction through stable epigenetic changes. Conversely, boosting bone morphogenetic protein (BMP) signaling while blocking TGFβ1 preserved effector and memory programs in chronically stimulated human CD8+ T cells, inducing superior responses to tumors and synergizing the ICB responses during chronic viral infection. Thus, rebalancing TGFβ1/BMP signals provides an exciting new approach to unleash dysfunctional CD8+ T cells and enhance T cell immunotherapies.
    DOI:  https://doi.org/10.1038/s41590-022-01384-y
  2. Nat Immunol. 2022 Dec 21.
    Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity.
    Paolo D A Vignali, Kristin DePeaux, McLane J Watson, Chenxian Ye, B Rhodes Ford, Konstantinos Lontos, Nicole K McGaa, Nicole E Scharping, Ashley V Menk, Simon C Robson, Amanda C Poholek, Dayana B Rivadeneira, Greg M Delgoffe.
      CD8+ T cells are critical for elimination of cancer cells. Factors within the tumor microenvironment (TME) can drive these cells to a hypofunctional state known as exhaustion. The most terminally exhausted T (tTex) cells are resistant to checkpoint blockade immunotherapy and might instead limit immunotherapeutic efficacy. Here we show that intratumoral CD8+ tTex cells possess transcriptional features of CD4+Foxp3+ regulatory T cells and are similarly capable of directly suppressing T cell proliferation ex vivo. tTex cell suppression requires CD39, which generates immunosuppressive adenosine. Restricted deletion of CD39 in endogenous CD8+ T cells resulted in slowed tumor progression, improved immunotherapy responsiveness and enhanced infiltration of transferred tumor-specific T cells. CD39 is induced on tTex cells by tumor hypoxia, thus mitigation of hypoxia limits tTex suppression. Together, these data suggest tTex cells are an important regulatory population in cancer and strategies to limit their generation, reprogram their immunosuppressive state or remove them from the TME might potentiate immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-022-01379-9
  3. Cancer Immunol Immunother. 2022 Dec 23.
    TCF-1 regulates NKG2D expression on CD8 T cells during anti-tumor responses.
    Rebecca Harris, Mahinbanu Mammadli, Shannon Hiner, Liye Suo, Qi Yang, Jyoti Misra Sen, Mobin Karimi.
      Cancer immunotherapy relies on improving T cell effector functions against malignancies, but despite the identification of several key transcription factors (TFs), the biological functions of these TFs are not entirely understood. We developed and utilized a novel, clinically relevant murine model to dissect the functional properties of crucial T cell transcription factors during anti-tumor responses. Our data showed that the loss of TCF-1 in CD8 T cells also leads to loss of key stimulatory molecules such as CD28. Our data showed that TCF-1 suppresses surface NKG2D expression on naïve and activated CD8 T cells via key transcriptional factors Eomes and T-bet. Using both in vitro and in vivo models, we uncovered how TCF-1 regulates critical molecules responsible for peripheral CD8 T cell effector functions. Finally, our unique genetic and molecular approaches suggested that TCF-1 also differentially regulates essential kinases. These kinases, including LCK, LAT, ITK, PLC-γ1, P65, ERKI/II, and JAK/STATs, are required for peripheral CD8 T cell persistent function during alloimmunity. Overall, our molecular and bioinformatics data demonstrate the mechanism by which TCF-1 modulated several critical aspects of T cell function during CD8 T cell response to cancer. Summary Figure: TCF-1 is required for persistent function of CD8 T cells but dispensable for anti-tumor response. Here, we have utilized a novel mouse model that lacks TCF-1 specifically on CD8 T cells for an allogeneic transplant model. We uncovered a molecular mechanism of how TCF-1 regulates key signaling pathways at both transcriptomic and protein levels. These key molecules included LCK, LAT, ITK, PLC-γ1, p65, ERK I/II, and JAK/STAT signaling. Next, we showed that the lack of TCF-1 impacted phenotype, proinflammatory cytokine production, chemokine expression, and T cell activation. We provided clinical evidence for how these changes impact GVHD target organs (skin, small intestine, and liver). Finally, we provided evidence that TCF-1 regulates NKG2D expression on mouse naïve and activated CD8 T cells. We have shown that CD8 T cells from TCF-1 cKO mice mediate cytolytic functions via NKG2D.
    Keywords:  Eomes and T-bet; GVHD; GVL; NKG2D; TCF-1
    DOI:  https://doi.org/10.1007/s00262-022-03323-0
  4. Immun Ageing. 2022 Dec 21. 19(1): 66
    Implication of IL-7 receptor alpha chain expression by CD8+ T cells and its signature in defining biomarkers in aging.
    Min Sun Shin, Hong-Jai Park, Juan Young, Insoo Kang.
      CD8+ T cells play an important role in host defense against infections and malignancies as well as contribute to the development of inflammatory disorders. Alterations in the frequency of naïve and memory CD8+ T cells are one of the most significant changes in the immune system with age. As the world population rapidly ages, a better understanding of aging immune function or immunosenescence could become a basis for discovering treatments of illnesses that commonly occur in older adults. In particular, biomarkers for immune aging could be utilized to identify individuals at high risk of developing age-associated conditions and help monitor the efficacy of therapeutic interventions targeting such conditions. This review details the possible role of CD8+ T cell subsets expressing different levels of the cytokine receptor IL-7 receptor alpha chain (IL-7Rα) and the gene signature associated with IL-7Rα as potential biomarkers for immune aging given the association of CD8+ T cells in host defense, inflammation, and immunosenescence.
    Keywords:  Aging; Biomarkers; CD8+ T cells; IL-7 receptor alpha chain; Signature
    DOI:  https://doi.org/10.1186/s12979-022-00324-6
  5. Cell Metab. 2022 Dec 12. pii: S1550-4131(22)00504-6. [Epub ahead of print]
    Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer.
    Hannah N Bell, Amanda K Huber, Rashi Singhal, Navyateja Korimerla, Ryan J Rebernick, Roshan Kumar, Marwa O El-Derany, Peter Sajjakulnukit, Nupur K Das, Samuel A Kerk, Sumeet Solanki, Jadyn G James, Donghwan Kim, Li Zhang, Brandon Chen, Rohit Mehra, Timothy L Frankel, Balázs Győrffy, Eric R Fearon, Marina Pasca di Magliano, Frank J Gonzalez, Ruma Banerjee, Daniel R Wahl, Costas A Lyssiotis, Michael Green, Yatrik M Shah.
      Effective therapies are lacking for patients with advanced colorectal cancer (CRC). The CRC tumor microenvironment has elevated metabolic waste products due to altered metabolism and proximity to the microbiota. The role of metabolite waste in tumor development, progression, and treatment resistance is unclear. We generated an autochthonous metastatic mouse model of CRC and used unbiased multi-omic analyses to reveal a robust accumulation of tumoral ammonia. The high ammonia levels induce T cell metabolic reprogramming, increase exhaustion, and decrease proliferation. CRC patients have increased serum ammonia, and the ammonia-related gene signature correlates with altered T cell response, adverse patient outcomes, and lack of response to immune checkpoint blockade. We demonstrate that enhancing ammonia clearance reactivates T cells, decreases tumor growth, and extends survival. Moreover, decreasing tumor-associated ammonia enhances anti-PD-L1 efficacy. These findings indicate that enhancing ammonia detoxification can reactivate T cells, highlighting a new approach to enhance the efficacy of immunotherapies.
    Keywords:  ammonia; cancer metabolism; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2022.11.013
  6. BMC Gastroenterol. 2022 Dec 21. 22(1): 533
    Markers of immune dysregulation in response to the ageing gut: insights from aged murine gut microbiota transplants.
    Panagiotis Giannos, Konstantinos Prokopidis, Masoud Isanejad, Helen L Wright.
       BACKGROUND: Perturbations in the composition and diversity of the gut microbiota are accompanied by a decline in immune homeostasis during ageing, characterized by chronic low-grade inflammation and enhanced innate immunity. Genetic insights into the interaction between age-related alterations in the gut microbiota and immune function remain largely unexplored.
    METHODS: We investigated publicly available transcriptomic gut profiles of young germ-free mouse hosts transplanted with old donor gut microbiota to identify immune-associated differentially expressed genes (DEGs). Literature screening of the Gene Expression Omnibus and PubMed identified one murine (Mus musculus) gene expression dataset (GSE130026) that included small intestine tissues from young (5-6 weeks old) germ-free mice hosts that were compared following 8 weeks after transplantation with either old (~ 24-month old; n = 5) or young (5-6 weeks old; n = 4) mouse donor gut microbiota.
    RESULTS: A total of 112 differentially expressed genes (DEGs) were identified and used to construct a gut network of encoded proteins, in which DEGs were functionally annotated as being involved in an immune process based on gene ontology. The association between the expression of immune-process DEGs and abundance of immune infiltrates from gene signatures in normal colorectal tissues was estimated from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) project. The analysis revealed a 25-gene signature of immune-associated DEGs and their expression profile was positively correlated with naïve T-cell, effector memory T-cell, central memory T-cell, resident memory T-cell, exhausted T-cell, resting Treg T-cell, effector Treg T-cell and Th1-like colorectal gene signatures. Conclusions These genes may have a potential role as candidate markers of immune dysregulation during gut microbiota ageing. Moreover, these DEGs may provide insights into the altered immune response to microbiota in the ageing gut, including reduced antigen presentation and alterations in cytokine and chemokine production.
    Keywords:  Ageing; Differentially expressed genes; Gut microbiota; Immune system; Inflammation; Innate immunity
    DOI:  https://doi.org/10.1186/s12876-022-02613-2
  7. Immunohorizons. 2022 Dec 01. 6(12): 837-850
    Acly Deficiency Enhances Myelopoiesis through Acetyl Coenzyme A and Metabolic-Epigenetic Cross-Talk.
    Dalton L Greenwood, Haley E Ramsey, Phuong T T Nguyen, Andrew R Patterson, Kelsey Voss, Jackie E Bader, Ayaka Sugiura, Zachary A Bacigalupa, Samuel Schaefer, Xiang Ye, Debolanle O Dahunsi, Matthew Z Madden, Kathryn E Wellen, Michael R Savona, P Brent Ferrell, Jeffrey C Rathmell.
      Hematopoiesis integrates cytokine signaling, metabolism, and epigenetic modifications to regulate blood cell generation. These processes are linked, as metabolites provide essential substrates for epigenetic marks. In this study, we demonstrate that ATP citrate lyase (Acly), which metabolizes citrate to generate cytosolic acetyl-CoA and is of clinical interest, can regulate chromatin accessibility to limit myeloid differentiation. Acly was tested for a role in murine hematopoiesis by small-molecule inhibition or genetic deletion in lineage-depleted, c-Kit-enriched hematopoietic stem and progenitor cells from Mus musculus. Treatments increased the abundance of cell populations that expressed the myeloid integrin CD11b and other markers of myeloid differentiation. When single-cell RNA sequencing was performed, we found that Acly inhibitor-treated hematopoietic stem and progenitor cells exhibited greater gene expression signatures for macrophages and enrichment of these populations. Similarly, the single-cell assay for transposase-accessible chromatin sequencing showed increased chromatin accessibility at genes associated with myeloid differentiation, including CD11b, CD11c, and IRF8. Mechanistically, Acly deficiency altered chromatin accessibility and expression of multiple C/EBP family transcription factors known to regulate myeloid differentiation and cell metabolism, with increased Cebpe and decreased Cebpa and Cebpb. This effect of Acly deficiency was accompanied by altered mitochondrial metabolism with decreased mitochondrial polarization but increased mitochondrial content and production of reactive oxygen species. The bias to myeloid differentiation appeared due to insufficient generation of acetyl-CoA, as exogenous acetate to support alternate compensatory pathways to produce acetyl-CoA reversed this phenotype. Acly inhibition thus can promote myelopoiesis through deprivation of acetyl-CoA and altered histone acetylome to regulate C/EBP transcription factor family activity for myeloid differentiation.
    DOI:  https://doi.org/10.4049/immunohorizons.2200086
  8. Microbiol Spectr. 2022 Dec 21. e0309122
    Regulation of Mitochondrial Energy Metabolism by Glutaredoxin 5 in the Apicomplexan Parasite Neospora caninum.
    Xingju Song, Xu Yang, Zhu Ying, Kaijian Wu, Jing Liu, Qun Liu.
      Iron-sulfur [Fe-S] clusters are one of the most ancient and functionally versatile natural biosynthetic prosthetic groups required by various proteins involved in important metabolic processes, including the oxidative phosphorylation of proteins, electron transfer, energy metabolism, DNA/RNA metabolism, and protein translation. Apicomplexan parasites harbor two possible [Fe-S] cluster assembly pathways: the iron-sulfur cluster (ISC) pathway in the mitochondria and the sulfur formation (SUF) pathway in the apicoplast. Glutaredoxin 5 (GRX5) is involved in the ISC pathway in many eukaryotes. However, the cellular roles of GRX5 in apicomplexan parasites remain to be explored. Here, we showed that Neospora caninum mitochondrial GRX5 (NcGRX5) deficiency resulted in aberrant mitochondrial ultrastructure and led to a significant reduction in parasite proliferation and virulence in mice, suggesting that NcGRX5 is important for parasite growth in vitro and in vivo. Comparative proteomics and energy metabolomics were used to investigate the effects of NcGRX5 on parasite growth and mitochondrial metabolism. The data showed that disruption of NcGRX5 downregulated the expression of mitochondrial electron transport chain (ETC) and tricarboxylic acid cycle (TCA) cycle proteins and reduced the corresponding metabolic fluxes. Subsequently, we identified 23 proteins that might be adjacent to or interact with NcGRX5 by proximity-based protein labeling techniques and proteomics. The interactions between NcGRX5 and two iron-sulfur cluster synthesis proteins (ISCS and ISCU1) were further confirmed by coimmunoprecipitation assays. In conclusion, NcGRX5 is important for parasite growth and may regulate mitochondrial energy metabolism by mediating the biosynthesis of iron-sulfur clusters. IMPORTANCE Iron-sulfur [Fe-S] clusters are among the oldest and most ubiquitous prosthetic groups, and they are required for a variety of proteins involved in important metabolic processes. The intracellular parasites in the phylum Apicomplexa, including Plasmodium, Toxoplasma gondii, and Neospora caninum, harbor the ISC pathway involved in the biosynthesis of [Fe-S] clusters in mitochondria. These cofactors are required for a variety of important biological processes. However, little is known about the role of oxidoreductase glutaredoxins in these parasites. Our data indicate that NcGRX5 is an essential protein that plays multiple roles in several biological processes of N. caninum. NcGRX5 interacts with the mitochondrial iron-sulfur cluster synthesis proteins ISCS and ISCU1 and also regulates parasite energy metabolism. These data provide an insider's view of the metabolic regulation and iron-sulfur cluster assembly processes in the apicomplexan parasites.
    Keywords:  Neospora caninum; energy metabolism; glutaredoxin 5; iron-sulfur cluster assembly
    DOI:  https://doi.org/10.1128/spectrum.03091-22
  9. Antioxidants (Basel). 2022 Dec 08. pii: 2426. [Epub ahead of print]11(12):
    NRF2/Itaconate Axis Regulates Metabolism and Inflammatory Properties of T Cells in Children with JIA.
    Anandhi Rajendiran, Sudheendra Hebbar Subramanyam, Patricia Klemm, Vera Jankowski, Jorg van Loosdregt, Bas Vastert, Kristina Vollbach, Norbert Wagner, Klaus Tenbrock, Kim Ohl.
       BACKGROUND: CD4+ T cells critically contribute to the initiation and perturbation of inflammation. When CD4+ T cells enter inflamed tissues, they adapt to hypoxia and oxidative stress conditions, and to a reduction in nutrients. We aimed to investigate how this distinct environment regulates T cell responses within the inflamed joints of patients with childhood rheumatism (JIA) by analyzing the behavior of NRF2-the key regulator of the anti-oxidative stress response-and its signaling pathways.
    METHODS: Flow cytometry and quantitative RT-PCR were used to perform metabolic profiling of T cells and to measure the production of inflammatory cytokines. Loss of function analyses were carried out by means of siRNA transfection experiments. NRF2 activation was induced by treatment with 4-octyl-Itaconate (4-OI).
    RESULTS: Flow cytometry analyses revealed a high metabolic status in CD4+ T cells taken from synovial fluid (SF) with greater mitochondrial mass, and increased glucose and fatty acid uptake. This resulted in a heightened oxidative status of SF CD4+ T cells. Despite raised ROS levels, expression of NRF2 and its target gene NQO1 were lower in CD4+ T cells from SF than in those from blood. Indeed, NRF2 activation of CD4+ T cells downregulated oxidative stress markers, altered the metabolic phenotype and reduced secretion of IFN-γ.
    CONCLUSION: NRF2 could be a potential regulator in CD4+ T cells during chronic inflammation and could instigate a drift toward disease progression or regression, depending on the inflammatory environment.
    Keywords:  JIA; NRF2; ROS; immunometabolism; redox metabolism
    DOI:  https://doi.org/10.3390/antiox11122426
  10. Viruses. 2022 Dec 11. pii: 2763. [Epub ahead of print]14(12):
    T Cell Transcriptional Signatures of Influenza A/H3N2 Antibody Response to High Dose Influenza and Adjuvanted Influenza Vaccine in Older Adults.
    Iana H Haralambieva, Huy Quang Quach, Inna G Ovsyannikova, Krista M Goergen, Diane E Grill, Gregory A Poland, Richard B Kennedy.
      Older adults experience declining influenza vaccine-induced immunity and are at higher risk of influenza and its complications. For this reason, high dose (e.g., Fluzone) and adjuvanted (e.g., Fluad) vaccines are preferentially recommended for people age 65 years and older. However, T cell transcriptional activity shaping the humoral immune responses to Fluzone and Fluad vaccines in older adults is still poorly understood. We designed a study of 234 older adults (≥65 years old) who were randomly allocated to receive Fluzone or Fluad vaccine and provided blood samples at baseline and at Day 28 after immunization. We measured the humoral immune responses (hemagglutination inhibition/HAI antibody titer) to influenza A/H3N2 and performed mRNA-Seq transcriptional profiling in purified CD4+ T cells, in order to identify T cell signatures that might explain differences in humoral immune response by vaccine type. Given the large differences in formulation (higher antigen dose vs adjuvant), our hypothesis was that each vaccine elicited a distinct transcriptomic response after vaccination. Thus, the main focus of our study was to identify the differential gene expression influencing the antibody titer in the two vaccine groups. Our analyses identified three differentially expressed, functionally linked genes/proteins in CD4+ T cells: the calcium/calmodulin dependent serine/threonine kinase IV (CaMKIV); its regulator the TMEM38B/transmembrane protein 38B, involved in maintenance of intracellular Ca2+ release; and the transcriptional coactivator CBP/CREB binding protein, as regulators of transcriptional activity/function in CD4+ T cells that impact differences in immune response by vaccine type. Significantly enriched T cell-specific pathways/biological processes were also identified that point to the importance of genes/proteins involved in Th1/Th2 cell differentiation, IL-17 signaling, calcium signaling, Notch signaling, MAPK signaling, and regulation of TRP cation Ca2+ channels in humoral immunity after influenza vaccination. In summary, we identified the genes/proteins and pathways essential for cell activation and function in CD4+ T cells that are associated with differences in influenza vaccine-induced humoral immunity by vaccine type. These findings provide an additional mechanistic perspective for achieving protective immunity in older adults.
    Keywords:  T cells; gene expression profiling; genetic markers; hemagglutination inhibition; humoral; immunity; influenza; influenza vaccine; transcriptome
    DOI:  https://doi.org/10.3390/v14122763
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