bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–02–23
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Lysosomal NKG7 restrains mTORC1 activity to promote CD8+ T cell durability and tumor control.
  2. Transcriptional control of T cell tissue adaptation and effector function in infants and adults.
  3. Metabolic and stress response adaptations in T cells to fever and physiological heat.
  4. CD4+ T-cell metabolism in the pathogenesis of Sjogren's syndrome.
  5. Enhanced paracrine action of FGF21 in stromal cells delays thymic aging.
  6. In a model of parasite-mediated exhaustion, stem-like CD8 T cells differentiate into an unconventional intermediate effector memory subset.
  7. Effect of binary mechanical environment on T cell function.
  8. Intrinsic STING of CD8 + T cells regulates self-metabolic reprogramming and memory to exert anti-tumor effects.
  9. IL-27 boosts cytotoxic T cells in cancer.
  10. Methionine intervention induces PD-L1 expression to enhance the immune checkpoint therapy response in MTAP-deleted osteosarcoma.
  11. Metabolic Adaptations Rewire CD4 T Cells in a Subset-Specific Manner in Human Critical Illness with and without Sepsis.
  12. EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models.
  13. Epigenetic attenuation of interferon signaling drives aging-related improvements in systemic lupus.
  1. Nat Commun. 2025 Feb 14. 16(1): 1628
    Lysosomal NKG7 restrains mTORC1 activity to promote CD8+ T cell durability and tumor control.
    Hyoungjun Ham, Jacob B Hirdler, Daniel T Bihnam, Zhiming Mao, Joanina K Gicobi, Bruna Gois Macedo, Maria F Rodriguez-Quevedo, Destiny F Schultz, Cristina Correia, Jun Zhong, Kodi E Martinez, Alma Banuelos, Dallin S Ashton, Anthony B Lagnado, Ruifeng Guo, Rodrigo Pessoa, Akhilesh Pandey, Hu Li, Fabrice Lucien, Henrique Borges da Silva, Haidong Dong, Daniel D Billadeau.
      During infection and cancer, mTORC1-mediated metabolic regulation impacts CD8+ T cell effector expansion and memory development. However, the mechanisms by which CD8+ T cells regulate mTORC1 to support their unique metabolic requirements remain unknown. Here we show that NKG7, a lysosomal protein whose expression is restricted to cytotoxic lymphocytes, negatively regulates mTORC1 recruitment and activation by inhibiting assembly and function of the lysosomal proton pump, vacuolar ATPase (v-ATPase). Human and mouse CD8+ T cells lacking NKG7 show more acidic lysosomes and increased activation of mTORC1 signaling, which could be reversed by inhibition of v-ATPase activity. In mice responding to LCMV infection, NKG7-deleted effector CD8+ T cells are less durable and generate fewer memory precursors, whereas induced expression of NKG7 in CD8+ T cells results in increased presence of intra-tumoral T cells. Overall, our work identifies NKG7 as a CD8+ T cell-specific regulator of mTORC1 activity, required for optimal immune responses.
    DOI:  https://doi.org/10.1038/s41467-025-56931-6
  2. bioRxiv. 2025 Feb 06. pii: 2025.02.01.636039. [Epub ahead of print]
    Transcriptional control of T cell tissue adaptation and effector function in infants and adults.
    Peter A Szabo, Hanna M Levitin, Thomas J Connors, David Chen, Jenny Jin, Puspa Thapa, Rebecca Guyer, Daniel P Caron, Joshua I Gray, Rei Matsumoto, Masaru Kubota, Maigan Brusko, Todd M Brusko, Donna L Farber, Peter A Sims.
      The first years of life are essential for the development of memory T cells, which rapidly populate the body's diverse tissue sites during infancy. However, the degree to which tissue memory T cell responses in early life reflect those during adulthood is unclear. Here, we use single cell RNA-sequencing of resting and ex vivo activated T cells from lymphoid and mucosal tissues of infant (aged 2-9 months) and adult (aged 40-65 years) human organ donors to dissect the transcriptional programming of memory T cells over age. Infant memory T cells demonstrate a unique stem-like transcriptional profile and tissue adaptation program, yet exhibit reduced activation capacity and effector function relative to adults. Using CRISPR-Cas9 knockdown, we define Helios ( IKZF2 ) as a critical transcriptional regulator of the infant-specific tissue adaptation program and restricted effector state. Our findings reveal key transcriptional mechanisms that control tissue T cell fate and function in early life.
    DOI:  https://doi.org/10.1101/2025.02.01.636039
  3. Trends Immunol. 2025 Feb 20. pii: S1471-4906(25)00025-0. [Epub ahead of print]
    Metabolic and stress response adaptations in T cells to fever and physiological heat.
    Benjamin A Wilander, Jeffrey C Rathmell.
      Fevers are an ancient feature of the inflammatory microenvironment. While fevers may improve the immune response to pathogens, mechanisms are unclear. We explore recent studies of how fever-range temperatures inform mammalian T cell metabolism, differentiation, and stress responses. Recent evidence indicates that metabolic programs initiated by fever are maintained upon return to thermo-normality, potentially providing a lasting benefit. Despite its impact, temperature remains overlooked and warrants further study. This is especially apparent when considering the wide temperature differential between tissues within the body and during inflammatory disease progression. We propose that differences in the metabolic and stress responses between T cell subsets upon thermal stress contribute to determining immune cell makeup and fate during inflammation.
    Keywords:  T cells; fever; immunometabolism; stress
    DOI:  https://doi.org/10.1016/j.it.2025.01.007
  4. Int Immunopharmacol. 2025 Feb 18. pii: S1567-5769(25)00310-8. [Epub ahead of print]150 114320
    CD4+ T-cell metabolism in the pathogenesis of Sjogren's syndrome.
    Baixi Chen, Chenji Zhang, Mengyuan Zhou, Hongyu Deng, Jiabao Xu, Junhao Yin, Changyu Chen, Dahe Zhang, Yiping Pu, Lingyan Zheng, Baoli Wang, Jiayao Fu.
      The abnormal effector function of CD4+ T cells plays a key role in the pathogenesis of Sjogren's syndrome (SS) and its associated systematic autoimmune response. Cellular metabolism, including glucose metabolism, lipid metabolism and amino acid metabolism, supports proliferation, migration, survival and differentiation into distinct CD4+ T-cell subsets. Different subtypes of T cells have significantly different demands for related metabolic processes, which enables us to finely regulate CD4+ T cells through different metabolic processes in autoimmune diseases such as SS. In this review, we summarize the effects of disturbances in distinct metabolic processes, such as glycolysis, fatty acid metabolism, glutamine decomposition, mitochondrial dynamics, and ferroptosis, on how to support the effector functions of CD4+ T cells in the SS. We also discuss potential drugs with high value in the treatment of SS through metabolic normalization in CD4+ T cells. Finally, we propose possible directions for future targeted therapy for immunometabolism in SS.
    Keywords:  Autoimmunity; Fatty acid; Glycolysis; Immunometabolism; OXPHOS; Sjogren's syndrome; T cell
    DOI:  https://doi.org/10.1016/j.intimp.2025.114320
  5. Nat Aging. 2025 Feb 19.
    Enhanced paracrine action of FGF21 in stromal cells delays thymic aging.
    Yun-Hee Youm, Christy Gliniak, Yuan Zhang, Tamara Dlugos, Philipp E Scherer, Vishwa Deep Dixit.
      Age-related thymic involution precedes aging of all other organs in vertebrates and initiates the process of declining T cell diversity, which leads to eventual immune dysfunction. Whether FGF21, a liver-derived pro-longevity hormone that is also produced in thymic stroma, including by adipocytes, controls the mechanism of thymic demise is incompletely understood. Here, we demonstrate that elevation of FGF21 in thymic epithelial cells (TECs) and in adipocytes protects against thymic aging, whereas conditional hepatic overexpression did not impact thymic biology in aged mice. Notably, elevation of thymic FGF21 increased naïve CD8 T cells in aged animals and extended healthspan. Mechanistically, thymic FGF21 overexpression elevated TECs and reduced fibroadipogenic cells. Ablation of β-klotho, the obligatory co-receptor for FGF21 in Foxn1+ TECs, accelerated thymic aging, suggesting regulation of TECs by FGF21 is partially required for thymic lymphopoiesis. These findings establish that paracrine FGF21 improves thymic function and delays immune aging.
    DOI:  https://doi.org/10.1038/s43587-025-00813-5
  6. bioRxiv. 2025 Jan 28. pii: 2024.10.30.621158. [Epub ahead of print]
    In a model of parasite-mediated exhaustion, stem-like CD8 T cells differentiate into an unconventional intermediate effector memory subset.
    Magali M Moretto, Keer Chen, Christina Cox, Jie Chen, Imtiaz A Khan.
      CD8 T cell exhaustion has been reported in mice susceptible to Toxoplasma gondii infection. While the differentiation of CD8 exhausted subsets has been extensively reported, most of these studies have been conducted in chronic viral and cancer models. During chronic T. gondii infection, phenotypic and transcriptomic analyses of the polyclonal antigen-specific CD8 T cell response characterize four populations based on KLRG1 and CD62L expression. Pop1 (KLRG1 + CD62L lo ) bears the attributes of a terminal effector subset, and pop2 (KLRG1 - CD62L lo ) is similar to effector memory CD8 T cells. Akin to chronic viral infection and cancer systems, pop3 (KLRG1 - CD62L hi ) exhibits the characteristics of stem-like progenitor CD8 T cells (high Tcf7, Slamf6, and Cxcr5 expression), whereas pop4 (KLRG1 + CD62L hi ) closely resembles a transitory subset (elevated Tbx21, low Tcf1, and Tox expression). During chronic viral infection, the stem-like progenitor CD8 T cells transition into a terminally differentiated exhausted subset via an intermediate population. However, in our system, pop3 generates pop4, which does not convert into a conventional terminally differentiated exhausted subset but instead transitions into effector pop1. Notably, during the chronic phase of the infection, pop1 cannot retain its functionality, irrespective of its origin, which may hamper its ability to control reactivation. Our observations emphasize that the differentiation of exhausted CD8 T cells in non-viral infections, like chronic toxoplasmosis, follows a different pattern than established models and highlights the need to develop new immune strategies better tailored for a broad range of pathogens.
    DOI:  https://doi.org/10.1101/2024.10.30.621158
  7. Acta Biomater. 2025 Feb 12. pii: S1742-7061(25)00114-X. [Epub ahead of print]
    Effect of binary mechanical environment on T cell function.
    Jatin Jawhir Pandit, Abed Al-Kader Yassin, Carlos Ureña Martin, Guillaume Le Saux, Angel Porgador, Mark Schvartzman.
      T cells, key players in the immune system, recognize antigens via T-cell receptors (TCRs) and require additional costimulatory and cytokine signals for full activation. Beyond biochemical signals, T cells also respond to mechanical cues such as tissue stiffness. Traditional ex-vivo mechanostimulating platforms, however, present a uniform mechanical environment, unlike the heterogeneous conditions T cells encounter in-vivo. This work introduces a mechanically-biphasic T-cell stimulating surface, with alternating soft and stiff microdomains, to mimic the complex mechanical signals T cells face. Results show that T cells exposed to this biphasic environment do not average the mechanical signals but instead respond similarly to those on a homogeneously soft surface, leading to lower activation compared to those on a stiff surface. Interestingly, long-term exposure to these patterns enhances the proliferation of central memory and effector T cell phenotypes, similar to stiff environments. These findings reveal the non-linear nature of T cell mechanosensing and suggest that mechanical heterogeneity plays a critical role in modulating T cell responses, providing new insights into T cell activation and potential implications for immunotherapies. STATEMENT OF SIGNIFICANCE: This research offers a fresh perspective in T cell mehanosensing, an important yet underexplored aspect of immunity. While previous studies have demonstrated that T cells sense homogeneous mechanical environments ex-vivo, their ability to discern and respond to simultaneous mechanical cues-resembling the complexity of in-vivo conditions-remained unexamined. By designing a mechanically patterned surface with alternating soft and stiff microdomains, this study simulates the diverse mechanical landscape encountered by T cells in-vivo. The findings reveal that T cells predominantly respond to this pattern as they would to a uniformly soft environment. This insight, showing that mechanical signals shape T cell activation and promote specific phenotypes, enhances our understanding of T cell biology and points to new directions for immunotherapy development.
    Keywords:  Biomaterials; CAR-T therapy; Fabrication; Immunotherapy; Mechanosensing; Nanofabrication; T-cell activation; T-cells
    DOI:  https://doi.org/10.1016/j.actbio.2025.02.029
  8. Cell Commun Signal. 2025 Feb 19. 23(1): 99
    Intrinsic STING of CD8 + T cells regulates self-metabolic reprogramming and memory to exert anti-tumor effects.
    Qiuli Xu, Xin Hua, Bingbing Li, Bei Jiang, Jiajia Jin, Ranpu Wu, Yanli Gu, Hao Xu, Qinpei Cheng, Suhua Zhu, Fang Zhang, Tangfeng Lv, Yong Song.
       BACKGROUND: Our team has previously found that the stimulator of interferon genes (STING) plays a more significant anti-tumor role in host immune cells than in tumor cells. Although STING is necessary for CD8 + T cells to exert immunological activity, its effect on CD8 + T cells remains debatable. In this study, we used both in vitro and in vivo models to explore the metabolic effects of STING on CD8 + T cells.
    METHODS: Peripheral blood lymphocytes were procured from non-small cell lung cancer (NSCLC) patients receiving anti-PD-1 therapy to investigate the correlation between STING expression levels, CD8 + T-cell subsets, and immunotherapy efficacy. STING knockout (STING-KO) mice were used for in vivo studies. RNA-seq, seahorse, flow cytometry, electron microscopy, qPCR, immunofluorescence, western blotting, and immunoprecipitation were performed to explore the underlying mechanisms of STING in regulating CD8 + T cell function.
    RESULTS: We discovered that the expression level of STING in immune cells exhibited a significant correlation with immunotherapy efficacy, as well as with the proportion of central memory CD8 + T cells. Moreover, we found that the loss of the STING gene results in a reduction in the number of mitochondria and a change in the metabolic pathway selection, thereby inducing excessive glycolysis in CD8 + T cells. This excessive glycolysis generates high levels of lactate, which further inhibits IFN-γ secretion and impacts memory T cell differentiation. Correcting the glycolysis disorder partially restored function and IFN-γ secretion, rescued the central memory CD8 + T subset, and improved immunotherapy in STING-KO mice. This provides a new treatment strategy for patients with low STING expression and a poor response to immunotherapy.
    CONCLUSION: Intrinsic STING of CD8 + T cells affects their function through the HK2/Lactate/IFN-γ axis and affects memory differentiation by regulating glycolysis.
    Keywords:  CD8 + T cells; Glycolysis; Immunotherapy; Metabolic reprogramming; Non-small cell lung cancer; STING
    DOI:  https://doi.org/10.1186/s12964-025-02069-3
  9. Nat Rev Immunol. 2025 Feb 14.
    IL-27 boosts cytotoxic T cells in cancer.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-025-01147-4
  10. Cell Rep Med. 2025 Feb 13. pii: S2666-3791(25)00050-3. [Epub ahead of print] 101977
    Methionine intervention induces PD-L1 expression to enhance the immune checkpoint therapy response in MTAP-deleted osteosarcoma.
    Haoran Mu, Qi Zhang, Dongqing Zuo, Jinzeng Wang, Yining Tao, Zhen Li, Xin He, Huanliang Meng, Hongsheng Wang, Jiakang Shen, Mengxiong Sun, Yafei Jiang, Weisong Zhao, Jing Han, Mengkai Yang, Zhuoying Wang, Yu Lv, Yuqin Yang, Jing Xu, Tao Zhang, Liu Yang, Jun Lin, Feng Tang, Renhong Tang, Haiyan Hu, Zhengdong Cai, Wei Sun, Yingqi Hua.
      Osteosarcoma (OS), a malignant bone tumor with limited treatment options, exhibits low sensitivity to immune checkpoint therapy (ICT). Through genomics and transcriptomics analyses, we identify a subgroup of OS with methylthioadenosine phosphorylase (MTAP) deletion, which contributes to ICT resistance, leading to a "cold" tumor microenvironment. MTAP-deleted OS relies on methionine metabolism and is sensitive to methionine intervention, achieved through either dietary restriction or inhibition of methionine adenosyltransferase 2a (MAT2A), a key enzyme in methionine metabolism. We further demonstrate that methionine intervention triggers programmed death-ligand 1 (PD-L1) transcription factor IKAROS family zinc finger 1 (IKZF1) and enhances PD-L1 expression in MTAP-deleted OS cells. Methionine intervention also activates the immune-related signaling pathways in MTAP-deleted OS cells and attracts CD8+ T cells, thereby enhancing the efficacy of ICT. Combining methionine intervention with ICT provides a significant survival benefit in MTAP-deleted OS murine models, suggesting a rationale for combination regimens in OS ICT.
    Keywords:  IKZF1; MAT2A; MTAP deletion; PD-L1; immunotherapy; methionine metabolism; osteosarcoma; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.xcrm.2025.101977
  11. bioRxiv. 2025 Jan 29. pii: 2025.01.27.635146. [Epub ahead of print]
    Metabolic Adaptations Rewire CD4 T Cells in a Subset-Specific Manner in Human Critical Illness with and without Sepsis.
    Matthew T Stier, Allison E Sewell, Erin L Mwizerwa, Chooi Ying Sim, Samantha M Tanner, Casey M Nichols, Heather H Durai, Erin Q Jennings, Paul Lindau, Erin M Wilfong, Dawn C Newcomb, Julie A Bastarache, Lorraine B Ware, Jeffrey C Rathmell.
      Host immunity in sepsis has features of hyperinflammation together with progressive immunosuppression, particularly among CD4 T cells, that can predispose to secondary infections and ineffectual organ recovery. Metabolic and immunologic dysfunction are archetypal findings in critically ill patients with sepsis, but whether these factors are mechanistically linked remains incompletely defined. We characterized functional metabolic properties of human CD4 T cells from critically ill patients with and without sepsis and healthy adults. CD4 T cells in critical illness showed increased subset-specific metabolic plasticity, with regulatory T cells (Tregs) acquiring glycolytic capacity that stabilized suppressive markers FOXP3 and TIGIT and correlated with clinical illness severity. Single-cell transcriptomics identified differential kynurenine metabolism in Tregs, which was validated ex vivo as a mechanism of Treg glycolytic adaptation and suppressive rewiring. These findings underscore immunometabolic dysfunction as a driver of CD4 T cell remodeling in sepsis and suggest therapeutic avenues to restore an effective immune response.
    DOI:  https://doi.org/10.1101/2025.01.27.635146
  12. Cancer Cell. 2025 Feb 20. pii: S1535-6108(25)00031-5. [Epub ahead of print]
    EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models.
    Patrizia Porazzi, Siena Nason, Ziqi Yang, Alberto Carturan, Guido Ghilardi, Puneeth Guruprasad, Ruchi P Patel, Melody Tan, Anushka Anant Padmanabhan, Jean Lemoine, Eugenio Fardella, Yunlin Zhang, Raymone Pajarillo, Linhui Chen, Ositadimma Ugwuanyi, Kelly Markowitz, Devora Delman, Mathew G Angelos, Olga Shestova, Yusuke Isshiki, Tatiana Blanchard, Wendy Béguelin, Ari M Melnick, Gerald P Linette, Gregory L Beatty, Beatriz M Carreno, Ivan Cohen, Luca Paruzzo, Stephen J Schuster, Marco Ruella.
      Tumor resistance to chimeric antigen receptor T cell (CAR-T) and, in general, to adoptive cell immunotherapies (ACTs) is a major challenge in the clinic. We hypothesized that inhibiting the tumor drivers' methyltransferases EZH2 and EZH1 could enhance ACT by rewiring cancer cells to a more immunogenic state. In human B cell lymphoma, EZH2 inhibition (tazemetostat) improved the efficacy of anti-CD19 CAR-T by enhancing activation, expansion, and tumor infiltration. Mechanistically, tazemetostat-treated tumors showed upregulation of genes related to adhesion, B cell activation, and inflammatory responses, and increased avidity to CAR-T. Furthermore, tazemetostat improved CAR- and TCR-engineered T cell efficacy in multiple liquid (myeloma and acute myeloid leukemia) and solid (sarcoma, ovarian, and prostate) cancers. Lastly, combined EZH1/EZH2 inhibition (valemetostat) further boosted CAR-T efficacy and expansion in multiple cancers. This study shows that EZH1/2 inhibition reprograms tumors to a more immunogenic state and potentiates ACT in preclinical models of both liquid and solid cancers.
    Keywords:  B cell lymphoma; CAR-T; EZH1; EZH2; T cell receptor; adoptive T cell therapy; chimeric antigen receptor T cells; epigenetics; multiple myeloma; solid cancers; tazemetostat; valemetostat
    DOI:  https://doi.org/10.1016/j.ccell.2025.01.013
  13. medRxiv. 2025 Jan 28. pii: 2025.01.27.25321143. [Epub ahead of print]
    Epigenetic attenuation of interferon signaling drives aging-related improvements in systemic lupus.
    Rithwik Narendra, Hoang Van Phan, Sarah L Patterson, Ana Laura Almonte Loya, Cristina Lanata, Christina Love, Joonsuk Park, Emily C Lydon, Michiko Ametani Shimoda, Lisa Barcellos, Honey Mekonen, Angela Detweiler, Padmini Deosthale, Norma Neff, Lindsey A Criswell, Lenka Maliskova, Walter Eckalbar, Gabriella Fragiadakis, Jinoos Yazdany, Maria Dall'Era, Patricia Katz, Chun Jimmie Ye, Marina Sirota, Charles R Langelier.
      In the general human population, aging is associated with a rise in systemic inflammation, primarily involving innate immune pathways related to interferon (IFN), toll-like receptor, and cytokine signaling. In systemic lupus erythematosus (SLE), a prototypical systemic autoimmune disease, aging is distinctly associated with improvements in disease activity, suggesting a unique relationship between aging and inflammation in this disease. Using a multi-omic approach incorporating transcriptional profiling, single cell RNA sequencing, proteomics and methylation analysis, we studied age-related changes in the immune profiles of 287 SLE patients between 20 and 83 years old, and compared the results against 928 healthy controls aged between 21 and 89 years old. In contrast to the increase in inflammatory gene expression that occurs with aging in most healthy adults, SLE patients exhibited the opposite. Most notable was a decrease in type I IFN signaling that was evident across multiple cell types, with CD56-dim natural killer (NK) cells, CD4 + effector memory T cells, and naïve B cells exhibiting the most significant differences. We found that aging in SLE patients was also associated with decreased IFN-α2 and IFN-λ1 levels, and differential methylation of the genome. Notably, of the genes both downregulated and hypermethylated with older age, IFN-related genes were disproportionately represented, suggesting that age-related decreases in IFN signaling were driven in part by epigenetic silencing. Both SLE patients and healthy controls demonstrated age-related declines in naïve T cells and lymphoid progenitor cells, but only SLE patients demonstrated age-related increases in CD56-dim NK cells. Taken together, our work provides new insight into the phenomenon of inflammaging and the unique clinical improvement in disease activity that occurs in SLE patients as they age.
    DOI:  https://doi.org/10.1101/2025.01.27.25321143
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