bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–11–16
fourteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Butyrate promotes T cell 'stemness' to support immunity to melanoma.
  2. Quiet custodians of CD8+ T cell fate.
  3. BACH2 and HIV: partners in crime?
  4. FOXO1-driven metabolic reprogramming of hematomal CD8+ T cells drives the expansion of perihematomal edema following intracerebral hemorrhage.
  5. Divergent Effects of Cytomegalovirus and Rheumatoid Arthritis on Senescent CD4+ T Cells.
  6. Functional and Metabolic Heterogeneity of Dendritic Cells in Self-Tolerance and Autoimmunity.
  7. CBX6 induces CD8+ T cell exhaustion and tumor development in esophageal squamous cell carcinoma through SMARCD1-mediated CCL8 secretion and lactate efflux.
  8. Aging and immunity.
  9. Targeting asparagine potentiates anti-PD-L1 immunotherapy in gastric cancer by enhancing CD8+ T cell anti-tumor response.
  10. Progenitor effects and unique transcriptomic signatures linked to differentiation phenotype in clonally expanded antigen-specific CD8 T memory stem cells.
  11. Tumor-associated disruption of T cell receptor signaling: lessons across cancers with implications for CLL.
  12. Reprogramming the tumor microenvironment to boost adoptive T cell therapy.
  13. Differential Regulation of TCR-Induced ZFP36 and ZFP36L1 Expression by Cyclosporin A in CD8+ T Cells.
  14. Limited vaccine-induced CD8+ T cell immunity in HIV-infected immunological nonresponders.
  1. Nat Rev Immunol. 2025 Nov 14.
    Butyrate promotes T cell 'stemness' to support immunity to melanoma.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-025-01245-3
  2. Nat Immunol. 2025 Nov 14.
    Quiet custodians of CD8+ T cell fate.
    Charalampos Spilianakis.
      
    DOI:  https://doi.org/10.1038/s41590-025-02334-0
  3. Trends Immunol. 2025 Nov 08. pii: S1471-4906(25)00283-2. [Epub ahead of print]
    BACH2 and HIV: partners in crime?
    Marie Armani-Tourret, Mathias Lichterfeld.
      HIV-1 persists lifelong despite effective antiretroviral therapy, yet the mechanisms underlying this persistence remain incompletely understood. Recent work by Wei et al. and Gao et al. reveals that the transcription factor BACH2 orchestrates CD4+ T cell memory programs fostering long-term memory formation while limiting effector differentiation, thereby promoting HIV-1 persistence.
    Keywords:  BACH2; HIV-1; reservoir persistence
    DOI:  https://doi.org/10.1016/j.it.2025.10.016
  4. Cell Mol Immunol. 2025 Nov 14.
    FOXO1-driven metabolic reprogramming of hematomal CD8+ T cells drives the expansion of perihematomal edema following intracerebral hemorrhage.
    Jie Lin, Honglei Ren, Youliang Wang, Hanzhi Yu, Zhili Chen, Xintong Yu, Zhuyu Gao, Yan Zheng, Quanhong Wu, Yizhe Zhang, Qijian Lin, Rui Li, Decai Tian, Zhigang Cai, Qiang Liu, Ying Fu.
      Intracerebral hemorrhage (ICH) causes hematoma formation, leading to PHE, which is associated with leukocyte mobilization and increased inflammation at the site of brain injury. However, the fate of accumulated leukocytes within the hematoma and their impact on PHE expansion remain unknown. We performed single-cell immune profiling of hematoma cells from patients with acute ICH and reported a distinct phenotypic transformation of CD8+ T cells within the hematoma during the first 24 h after onset. In addition to enhanced IFN-γ production and migration capacity, these CD8+ T cells displayed remarkable glycolytic signatures. The metabolic fitness and functional reprogramming of hematomal CD8+ T cells are associated with the transcription factor FOXO1. Single-cell profiling of brain-infiltrating CD8+ T cells within the perihematomal tissues of ICH patients and cell culture assays revealed their capacity to activate microglia via the production of IFN-γ. Furthermore, the removal of hematomal CD8+ T cells reduced neuroinflammation, PHE expansion and neurological deficits in ICH mice. Thus, CD8+ T cells undergo metabolic and functional reprogramming within the hematoma during the acute phase of ICH, which contributes to PHE formation and neurological deterioration.
    Keywords:  CD8+ T cells; Hematoma; Intracerebral hemorrhage; Neuroinflammation; Perihematomal edema
    DOI:  https://doi.org/10.1038/s41423-025-01363-x
  5. Eur J Immunol. 2025 Nov;55(11): e70093
    Divergent Effects of Cytomegalovirus and Rheumatoid Arthritis on Senescent CD4+ T Cells.
    Lea Williams, Ali O Saber, Silina Awad, Xi Su, Asgar Ansari, Ruozhang Xu, Hannah Jung, Anupama Shahane, Joshua F Baker, Laura F Su.
      Chronic antigen exposure drives CD4⁺ T cell senescence, yet how autoimmunity and persistent viral infections differentially shape T cell differentiation and function remains unclear. Using cytomegalovirus (CMV) and rheumatoid arthritis (RA) as models of chronic immune activation, we performed high-dimensional mass cytometry and functional assays to define their impact on CD4⁺ T cells. In CMV-seropositive individuals, CD27-CD28- CD4⁺ T cells were abundant and exhibited a predominantly cytotoxic, nonproliferative phenotype. Only a minor fraction was CMV-reactive, suggesting that bystander-driven differentiation contributes to this subset. In the absence of CMV, senescent CD4⁺ T cells were infrequent and phenotypically distinct, though they still exhibited low proliferative capacity. EBV and HSV did not independently increase CD27-CD28- CD4⁺ T cell frequency. Similarly, RA had little effect on their abundance but instead tuned the functional quality of senescent cells. In CMV-seropositive RA patients, senescent CD4⁺ T cells produced less pro-inflammatory cytokines and showed impaired cytotoxic degranulation. Central memory CD4⁺ and CD27-CD28- CD8⁺ T cell functions were preserved, with no evidence for CMV reactivation, suggesting maintained viral control by unaffected T cell responses. These findings highlight distinct, nonredundant effects of CMV and RA on CD4⁺ T cell senescence and reveal RA-specific functional defects in senescent CD4⁺ T cells.
    DOI:  https://doi.org/10.1002/eji.70093
  6. Immunol Rev. 2025 Nov;336(1): e70068
    Functional and Metabolic Heterogeneity of Dendritic Cells in Self-Tolerance and Autoimmunity.
    Jianru Chen, Juan Liu, Xuetao Cao.
      Dendritic cells (DCs) demonstrate remarkable functional and metabolic heterogeneity that governs the balance between immune tolerance and autoimmune pathogenesis. Under homeostatic conditions, tolerogenic DC subsets maintain immunological equilibrium through distinct metabolic programs and the production of immunoregulatory metabolites, promoting T cell anergy and regulatory T cell (Treg) differentiation. In contrast, autoimmune conditions trigger pathogenic metabolic rewiring, shifting DCs toward glycolysis and enhanced lipid synthesis, which drives DC hyperactivation and breakdown of self-tolerance. This metabolic reprogramming is coordinately regulated by external microenvironmental cues and internal signaling pathways, leading to heterogeneous DC responses in diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and psoriasis. Targeting metabolic regulators offers promising therapeutic strategies to restore immune tolerance and prevent harmful autoimmunity and inflammation. The review highlights the intricate interplay between DC metabolism and function, emphasizing how metabolic heterogeneity underpins their dual roles in immune regulation and autoimmunity. Future exploration of subset-specific metabolic preferences and spatiotemporal metabolic dynamics will facilitate the development of precision immunotherapies for autoimmune diseases.
    Keywords:  autoimmunity; dendritic cell; immune homeostasis; immunometabolism; self‐tolerance
    DOI:  https://doi.org/10.1111/imr.70068
  7. Cell Biol Toxicol. 2025 Nov 12. 41(1): 150
    CBX6 induces CD8+ T cell exhaustion and tumor development in esophageal squamous cell carcinoma through SMARCD1-mediated CCL8 secretion and lactate efflux.
    Lihua Wang, Guoqing Liu, Qilan Huang, Haijing Wu, Xinhan Cheng, Li Pan.
      This study investigates the functions of chromobox 6 (CBX6) in esophageal squamous cell carcinoma (ESCC) and delves into its functional mechanisms. The bioinformatics insights suggested that CBX6 was overexpressed in ESCC and linked to dismal prognosis. Cbx6 knockdown was induced in mouse mEC25 cells. This procedure curbed the proliferation and migration of mEC25 cells and reduced exhaustion of the co-cultured CD8+ T cells. In vivo, Cbx6 knockdown in mEC25 cells reduced tumorigenesis while enhancing immune activity in mice. Further experiments showed that CBX6 reduced CD8+ T cell cytotoxicity by secreting C-C motif chemokine ligand 8 (CCL8) and promoting monocarboxylate transporter 4 (MCT4)-mediated lactate transport. Regarding the mechanism, CBX6 regulated the expression of SWI/SNF related BAF chromatin remodeling complex subunit D1 (Smarcd1) to modulate chromatin remodeling, thus promoting transcription of Ccl8 and Slc16a3 (encoding MCT4). Smarcd1 overexpression restored metabolic activity in mEC25 cells, reduced activity of co-cultured CD8+ T cells, and promoted tumorigenesis in vivo. Tissue microarrays analysis suggested that CBX6 and SMARCD1 were linked to immunosuppression and poor prognosis in clinical samples. In conclusion, this study suggests that CBX6 induces CD8+ T cell exhaustion and tumor development in ESCC through SMARCD1-mediated CCL8 secretion and lactate efflux.
    Keywords:  CBX6; CCL8; CD8+ T cell exhaustion; ESCC; MCT4; SMARCD1
    DOI:  https://doi.org/10.1007/s10565-025-10102-x
  8. Immunity. 2025 Nov 11. pii: S1074-7613(25)00473-X. [Epub ahead of print]58(11): 2609-2612
    Aging and immunity.
    Christoph A Thaiss, Ye Tian, Daniel A Winer, Michelle Linterman, Adrian Liston, Corina Amor, Scott W Lowe, Guang-Hui Liu.
      Time marches endlessly on … but what does that mean for the immune system? Here, investigators discuss how aging impacts the immune response and how immune cells can shape the aging process, with broader implications for modifying immunity to improve not only longevity but also health span.
    DOI:  https://doi.org/10.1016/j.immuni.2025.10.019
  9. Front Immunol. 2025 ;16 1626581
    Targeting asparagine potentiates anti-PD-L1 immunotherapy in gastric cancer by enhancing CD8+ T cell anti-tumor response.
    Mingpai Ge, Longfei Wang, Bowen Zheng, Lu Zhan, Lu Cui, Han Wang, Enyuan Huang, Yuan Xu, Xusheng Chang, Zhaorui Liu, Jun Xu, Kai Yin.
       Introduction: Immunotherapy efficacy in gastric cancer (GC) is often constrained by the tumor microenvironment (TME), which is profoundly influenced by aberrant metabolism. Asparagine, an amino acid critical for neoplastic proliferation, also modulates CD8+ T cell metabolic programming. We investigated the impact of targeting asparagine on the GC immune microenvironment and its potential to synergize with anti-PD-L1 therapy.
    Methods: The therapeutic efficacy of asparagine targeting was evaluated in GC tumor models. CD8+ T cell populations within the TME were analyzed by flow cytometry, while cytokine and chemokine levels (IFN-γ, GZMB, CXCL9, CXCL10) were quantified by ELISA. The effects on CD8+ T cell activation and antitumor function were assessed in vitro and in vivo. Synergistic efficacy with anti-PD-L1 therapy was evaluated in GC models, and the dependency on CD8+ T cells was confirmed via antibody-mediated depletion experiments.
    Results: Targeting asparagine inhibited GC growth in vitro and in vivo, implicating immune system involvement. Mechanistically, asparagine targeting significantly increased the proportion of CD8+ T cells within the TME and upregulated the expression of IFN-γ, GZMB, CXCL9, and CXCL10. Furthermore, combining asparagine targeting with anti-PD-L1 therapy produced synergistic antitumor activity. This combined therapeutic effect was significantly attenuated by the depletion of CD8+ T cells.
    Discussion: Our findings indicate that targeting asparagine promotes CD8+ T cell activation and infiltration, thereby remodeling the GC immune microenvironment to enhance host antitumor immunity. The combination of asparagine targeting with anti-PD-L1 therapy elicits potent, synergistic antitumor effects that are demonstrably dependent on CD8+ T cells. This study provides a strong rationale for targeting asparagine metabolism as a novel strategy to improve immunotherapeutic outcomes in GC.
    Keywords:  CD8 T cell; TME (tumor microenvironment); asparagine; gastric cancer; immunotherapy; metabolism
    DOI:  https://doi.org/10.3389/fimmu.2025.1626581
  10. J Immunol. 2025 Nov 13. pii: vkaf299. [Epub ahead of print]
    Progenitor effects and unique transcriptomic signatures linked to differentiation phenotype in clonally expanded antigen-specific CD8 T memory stem cells.
    Yanran Zhao, Jerome Samir, Elizabeth Keoshkerian, Hui Li, Hongyan An, Rowena A Bull, Fabio Luciani, Andrew R Lloyd.
      Memory stem CD8+ T cells (TSCM) are a long-lived T-cell subset with stem cell-like properties, playing a key role in antiviral immunity. Despite their importance, comprehensive single-cell transcriptomic profiling of antigen-specific TSCM has not been previously conducted. In this study, an in vitro single-cell colony expansion protocol was used to investigate human CD8+ T-cell clones specific for cytomegalovirus (CMV) epitopes. Clonal lineages from selected donors were generated by single-cell sorting of dextramer-positive CD8+ T cells with varied effector and memory phenotypes, all specific for one of 2 HLA-restricted CMV epitopes. Phenotypic and functional characterization of clonal lineages derived from antigen-specific TSCM revealed differentiated memory and effector subsets (TCM, TEM, TEMRA) as well as TSCM, with the latter subset featuring multi-potentiality and multi-cytokine production. Studying TSCM-derived progeny of these varied differentiation phenotypes in single-cell transcriptomic analysis revealed strong progenitor-to-progeny effects, whereby daughter cells from a shared progenitor clustered closely regardless of progeny differentiation phenotype, suggesting a dominant impact associated with heritable genes. TSCM-derived progeny that retained a TSCM phenotype expressed canonical early-memory genes such as IL7R, CCR7, SELL, and CD27, along with novel transcripts consistently shared across donors and epitopes. The transcriptional features of clonal lineages are strongly dependent on the progenitor cell, but TSCM have an additional transcriptomic signature, likely underpinning their unique differentiation and functional characteristics. These findings have important implications for identification of long-lived and multipotent CD8 T cells for immunotherapy and immunization against viral infections.
    Keywords:  CD8 T cell; clonal lineage; heritability; scRNA-seq; stem cell memory T cells
    DOI:  https://doi.org/10.1093/jimmun/vkaf299
  11. Leuk Lymphoma. 2025 Nov 14. 1-9
    Tumor-associated disruption of T cell receptor signaling: lessons across cancers with implications for CLL.
    Carlota Lopez-Sanchez, Jaco A C van Bruggen, Arnon P Kater.
      In chronic lymphocytic leukemia (CLL), T cell dysfunction is a hallmark feature and includes impaired proliferation, reduced cytotoxicity, defective immunological synapse formation, and metabolic exhaustion. While these alterations have been well described, the underlying mechanisms remain incompletely understood. By contrast, in the field of solid tumor immunotherapy, extensive research has yielded detailed mechanistic insights into how tumors evade T cell immunity, particularly by interfering with T cell receptor (TCR) signaling at multiple levels. This review examines whether the mechanisms of T cell dysfunction uncovered in solid oncology can inform our understanding of T cell failure in CLL. By aligning TCR defects in CLL with insights from solid tumors, we identify mechanistic explanations for T cell failure in CLL that warrant further investigation. These include non-canonical checkpoint signaling, recruitment of inhibitory phosphatases, and impaired propagation of activation signals. Understanding these pathways may enable rational design of next-generation immunotherapies for CLL.
    Keywords:  Chronic lymphocytic leukemia; T cell dysfunction; T cell receptor; signal transduction; solid malignancies; tumor microenvironment
    DOI:  https://doi.org/10.1080/10428194.2025.2587786
  12. Front Immunol. 2025 ;16 1677548
    Reprogramming the tumor microenvironment to boost adoptive T cell therapy.
    Maria Fernanda Meza Pacheco, Lee-Hwa Tai.
      Adoptive T cell therapies (ACT) have revolutionized the management of hematologic malignancies; however, their efficacy in solid tumors remains limited. Accumulating evidence implicates the tumor microenvironment (TME) - a highly complex and immunosuppressive niche as a major barrier to their effectiveness. In this review, we propose that the next generation of ACT will require a fundamental shift from a reductionist focus on T cell engineering alone to an integrated approach that considers the interactions between immune cells and the TME. A comprehensive literature review identified several emerging strategies to enhance the efficacy of ACT, including reprogramming tumor vasculature, repolarizing immunosuppressive myeloid and stromal cells, leveraging oncolytic viruses to remodel antigen presentation, inducing acute sterile inflammation, and targeting the physical properties of the extracellular matrix. While many of these approaches remain in early-stage development, some have already progressed to clinical trials, indicating their potential for clinical translation. Additionally, we found that conventional therapies, such as surgery, chemotherapy, and radiotherapy, can be strategically integrated with ACT to improve therapeutic outcomes. These findings highlight a shift in the field toward more integrative approaches. Future advances will likely depend on reprogramming the TME to support T cell persistence and functions. Addressing these interconnected challenges will require closer collaboration between immunology, oncology, and bioengineering disciplines.
    Keywords:  CAR (chimeric antigen receptor) T-cell therapy; adoptive T cell immunotherapy; immunomodulation; immunotherapy; oncology; tumor infiltrating lymphocyte; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1677548
  13. Eur J Immunol. 2025 Nov;55(11): e70085
    Differential Regulation of TCR-Induced ZFP36 and ZFP36L1 Expression by Cyclosporin A in CD8+ T Cells.
    Marian Jones Evans, Twm J Mitchell, Magdalena Zaucha, Georg Petkau, Martin Turner.
      CD8+ T cells target infected or malignant cells via the production of pro-inflammatory cytokines and direct target cell killing. Members of the ZFP36-family of RNA-binding proteins, ZFP36 and ZFP36L1, regulate these functions in T cells via the regulation of mRNA stability and protein translation. We investigate the regulation of ZFP36 and ZFP36L1 expression using in vitro differentiated OT1 TCR transgenic memory-like T cells. We characterise the differential kinetics and sensitivity of ZFP36 and ZFP36L1 to antigen affinity and PMA versus ionomycin stimulation. By selectively inhibiting TCR-induced signalling pathways, we find that p38 MAPK, MEK1/2, and PKC contribute to inducing both ZFP36 and ZFP36L1 expression. By contrast, inhibition of calcineurin using cyclosporin A potently inhibits ZFP36L1 expression while increasing and prolonging ZFP36 expression. The Zfp36 promoter contains many binding sites for the transcription factors ELK-1/4 and few binding sites for NFAT, while the Zfp36l1 promoter contains many NFAT binding sites and few ELK1/4 binding sites. Our findings suggest that the regulation of divergent transcription factors enables calcineurin to act as a signalling node that mediates the differential regulation of ZFP36 and ZFP36L1 during T cell activation.
    Keywords:  CD8 T cells; T cell activation; T cell signalling; ZFP36; ZFP36L1
    DOI:  https://doi.org/10.1002/eji.70085
  14. JCI Insight. 2025 Nov 10. pii: e195458. [Epub ahead of print]10(21):
    Limited vaccine-induced CD8+ T cell immunity in HIV-infected immunological nonresponders.
    Vivien Karl, Anne Graeser, Anastasia Kremser, Liane Bauersfeld, Florian Emmerich, Nadine Herkt, Siegbert Rieg, Susanne Usadel, Bertram Bengsch, Tobias Boettler, Hendrik Luxenburger, Christoph Neumann-Haefelin, Matthias C Müller, Robert Thimme, Maike Hofmann.
      BACKGROUNDAmong people living with HIV (PLWH), immunological nonresponders (INR) fail to adequately restore CD4+ T cell counts despite effective antiretroviral therapy (ART), placing them at greater risk for adverse outcomes and reduced vaccine efficacy. We aimed to study the robustness and longevity of vaccine-induced virus-specific cellular immune responses in INR.METHODSVirus-specific CD8+ T cell responses were analyzed in INR (CD4+ T cell count < 300 cells/μL) and immunological responders (IR) (CD4+ T cell count > 500 cells/μL), receiving ART, and HIV-uninfected controls following COVID-19 mRNA vaccination and infection. Virus-specific CD8+ T cells were characterized using peptide-loaded MHC I tetramer technology, after in vitro expansion and cytokine production assays. Virus-specific CD4+ T cells and IgG levels were determined by activation-induced marker (AIM) assay and ELISA, respectively.RESULTSWe demonstrated that, while long-lasting virus-specific cellular immune responses were generated in INR, CD8+ T cell immunity remained limited compared with robust CD4+ T cell reactivity. CD8+ T cell responses in INR exhibited reduced breadth and frequency, accompanied by altered memory differentiation and suboptimal activation and effector response upon antigen exposure. This deficiency correlated with low CD4+ T cell counts, independent of other disease markers, highlighting the pivotal role of CD4+ T cells in orchestrating vaccine-induced immunity. Notably, repeated booster vaccinations enhanced virus-specific CD8+ T cell responses.CONCLUSIONINR elicit limited vaccine-induced virus-specific CD8+ T cell immunity, but booster vaccinations can enhance these responses, suggesting better immune outcomes with tailored vaccination strategies.FUNDINGHelmholtz Society, German Research Foundation, Federal Ministry of Education and Research.
    Keywords:  AIDS/HIV; Adaptive immunity; Immunology; T cells; Vaccines; Virology
    DOI:  https://doi.org/10.1172/jci.insight.195458
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