bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–11–23
twenty papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Analysis of the three-dimensional genome of exhausted CD8+ T cells reveals a critical role of IRF8 in their differentiation and functions in cancer.
  2. Multimodal cell-cell communication driving CD8+ T cell dysfunction and immune evasion.
  3. CAR-T cell therapy for solid tumors: HIF-1α as a potential enhancement strategy.
  4. Thrombospondin-1-CD47 signaling contributes to the development of T cell exhaustion in cancer.
  5. Upregulation of TNFR2 Precedes TOX Expression by Exhausted T cells and Restricts Antitumor and Antiviral Immunity.
  6. Dysregulation of apolipoprotein o reprograms CCR7+CD4+T cell fate in primary autoimmune thrombocytopenia.
  7. Methionine regulates antitumor function of CD8 + T cells through polyamine synthesis.
  8. High glucose-induced mitophagy accelerates premature aging of T cells in patients with rheumatoid arthritis.
  9. Obesity rewires CD8+ T cell iron metabolism in adipose tissue to fuel metabolic inflammation.
  10. CD47 induces T cell exhaustion through interaction with thrombospondin-1.
  11. Astragalus polysaccharide promotes CD8 + T cell activity by downregulating Tim-3 to potentiate antitumor immunity.
  12. MDR1 promotes CD8 T cell persistence in tumors and protects against cytotoxic chemotherapy.
  13. Hepatocyte mitochondrial NAD+ content is limiting for liver regeneration.
  14. Senescent CD4+ T cells and autoimmune diseases: Mechanisms and therapeutic prospects.
  15. Tumour-reactive heterotypic CD8 T cell clusters from clinical samples.
  16. Reframing IL-27: a central regulator of CD8+ T cell immunity.
  17. Mitochondria in the immune system: Therapeutic potential from mitochondria transfer.
  18. SLC7A8 is essential for metabolic fitness and function of Th2 cells.
  19. Author Correction: CD8+ T cells induce cachexia during chronic viral infection.
  20. PTEN deficiency impairs IL-15-dependent T-cell immunity against prostate cancer.
  1. Nat Immunol. 2025 Nov 18.
    Analysis of the three-dimensional genome of exhausted CD8+ T cells reveals a critical role of IRF8 in their differentiation and functions in cancer.
    Ruifeng Li, Kun Wei, Qinli Sun, Bowen Xie, Peng Wei, Tian Xie, Xinyi Guo, Yongzhen Chen, Birui Pan, Zixuan Zhao, Ling Ni, Chen Dong.
      CD8+ T cells are rendered exhausted in cancer, accompanied by extensive changes in the epigenome. However, whether and how higher-order chromatin organization is involved in exhausted CD8+ T cell differentiation is unclear. Here, we show extensive changes in the three-dimensional genome during T cell exhaustion associated with changes in gene transcription. Moreover, we identified interferon regulatory factor 8 (IRF8) as an essential transcription factor involved in reorganization of the spatial proximity between enhancers and promoters of genes associated with exhausted T cell differentiation. IRF8 deficiency inhibited the differentiation of exhausted CD8+ T cells and their antitumor function. Mechanistically, IRF8 bound to genes associated with exhausted T cell differentiation and promoted the formation of intra-TAD chromosomal loops. At the loop anchor regions, IRF8 recruited CTCF to form active chromosomal structures to regulate gene transcription. These results thus identify a critical role of IRF8-dependent chromatin topology during exhausted CD8+ T cell differentiation.
    DOI:  https://doi.org/10.1038/s41590-025-02330-4
  2. Front Immunol. 2025 ;16 1691746
    Multimodal cell-cell communication driving CD8+ T cell dysfunction and immune evasion.
    Liping Chen, Qianping Huang, Peipei Zhou.
      Effective anti-tumor immunity critically depends on functional CD8+ T cells, yet in almost all solid tumors, these cells become dysfunctional, exhausted, or spatially excluded. This breakdown of immune surveillance arises not only from cell-intrinsic T cell exhaustion but also from multimodal communication among tumor, stromal, and immune cells within the tumor microenvironment (TME). This communication is mediated not only through direct receptor-ligand interactions but also through a suite of indirect mechanisms, such as metabolic competition, secretion of immunosuppressive metabolites and cytokines, extracellular vesicle exchange, and even mitochondrial transfer via tunneling nanotubes or membrane transfer through T cell trogocytosis. Together, these suppressive interactions impair CD8+ T cell metabolism, effector function, and persistence, thereby enabling tumor immune evasion. In this review, we summarize current understanding of how multimodal cell-cell communication, including immune checkpoints, metabolic reprogramming, and stromal crosstalk, cooperatively drive CD8+ T cell dysfunction. We also highlight emerging therapeutic strategies aimed at rewiring these suppressive networks, with emphasis on translational potential. A deeper understanding of the spatial, molecular, and metabolic context of CD8+ T cell suppression offers new avenues to enhance the efficacy of cancer immunotherapies.
    Keywords:  CD8+ T cell; dysfunction; multimodal cell-cell communication; suppression; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1691746
  3. Autoimmunity. 2025 Dec;58(1): 2579069
    CAR-T cell therapy for solid tumors: HIF-1α as a potential enhancement strategy.
    Hai Rong Li, Jie Xiong, Chun Hui Wang, Li Bing Hu, Ying Bao Wang, Qin Rong Ping, Meng Yang, Jun Tan, Ting Ting Li, Yang Yang.
      The advent of chimeric antigen receptor (CAR) T cell therapy has yielded transformative efficacy in hematological malignancies, yet its application in solid tumors remains constrained by the immunosuppressive tumor microenvironment (TME). Characterized by hypoxia, acidosis, and nutrient deprivation, the TME critically compromises CAR-T cell infiltration, persistence, and effector functions. Hypoxia-inducible factor 1α (HIF-1α), a central regulator of cellular adaptation to hypoxia within the TME, modulates T cell metabolism and functionality-presenting a strategic framework for enhancing CAR-T cell efficacy in solid malignancies. This review characterizes the role of HIF-1α in reprogramming the tumor-immune microenvironment, with specific emphasis on its metabolic regulation of T cells and translational implications for CAR-T therapy. Under hypoxic stress, HIF-1α orchestrates a metabolic shift toward glycolysis in effector T cells by suppressing oxidative phosphorylation (OXPHOS) while upregulating key glycolytic enzymes (e.g. GLUT1, HK2, LDHA). This adaptation sustains ATP production while attenuating mitochondrial reactive oxygen species (ROS) accumulation, thereby mitigating T cell exhaustion and augmenting cytotoxic persistence. This HIF-1α-mediated metabolic reprogramming provides critical insights for overcoming barriers to CAR-T cell efficacy in solid tumors.
    Keywords:  CAR-T cells; HIF-1α; immunotherapy; solid tumor treatment; tumor microenvironment
    DOI:  https://doi.org/10.1080/08916934.2025.2579069
  4. Nat Immunol. 2025 Nov 17.
    Thrombospondin-1-CD47 signaling contributes to the development of T cell exhaustion in cancer.
    Chien-Huan Weng, Anais Assouvie, Lauren Dong, Jean-Christophe Beltra, Sadna Budhu, Levi Mangarin, Yacine Marouf, Lucia Morgado-Palacin, Cailian Liu, Sébastien Monette, Jonathan F Khan, Isabell Schulze, Dmitriy Zamarin, Linda Hamadene, Fadi Samaan, Daniel Hirschhorn, Stephane Pourpe, David Schröder, Roberta Zappasodi, Pamela M Holland, Niroshana Anandasabapathy, E John Wherry, Jedd D Wolchok, Taha Merghoub.
      T cell exhaustion is a major barrier to effective cancer immunotherapy. Although immune checkpoint blockade can reinvigorate exhausted T cells, not all patients achieve long-term responses, partly due to the refractory nature of terminally exhausted T cells. Beyond persistent antigen stimulation, the environmental drivers of exhaustion remain to be thoroughly characterized. Here we identify CD47 upregulation in tumor-infiltrating exhausted CD8+ T cells in both human and murine tumors. We reveal a novel role for the extracellular matrix protein thrombospondin-1 (TSP-1) in engaging CD47 on T cells to promote exhaustion. This interaction activates calcineurin-NFAT signaling, inducing upregulation of TOX and expression of inhibitory receptors, and impairing effector function during tumor progression. Importantly, disrupting the TSP-1-CD47 axis prevents T cell exhaustion and enhances tumor control. Our findings identify a novel pathway promoting T cell dysfunction and suggest that targeting the TSP-1-CD47 axis is a promising strategy to enhance T cell immunity and immunotherapy efficacy.
    DOI:  https://doi.org/10.1038/s41590-025-02321-5
  5. Clin Cancer Res. 2025 Nov 21.
    Upregulation of TNFR2 Precedes TOX Expression by Exhausted T cells and Restricts Antitumor and Antiviral Immunity.
    Alexandra M Hoyt-Miggelbrink, Jessica Waibl Polania, Luke Wachsmuth, Selena Lorrey, Aditya Mohan, Andrew Hardigan, Emily Blandford, Emily Lerner, Daniel Wilkinson, Kelly M Hotchkiss, Sarah Cook, Saskia Hemmers, Anoop Patel, Katayoun Ayasoufi, Peter Fecci.
       PURPOSE: Exhaustion represents a collection of programmed T cell differentiation states and an important mode of T cell dysfunction. T cell progression from progenitor to terminal exhaustion is associated with upregulation of the transcription factor TOX. Our understanding of factors regulating TOX expression and the transition from progenitor to terminal exhaustion, however, remains incomplete.
    EXPERIMENTAL DESIGN: Single-cell RNA sequencing was used to evaluate expression of TNF receptors on human and murine tumor-infiltrating CD8+ T cells. Flow cytometry was utilized to assess exhaustion markers and TNF receptors on CD8+ T cells. Bulk RNA sequencing was used to demonstrate the role of TNFR2 on the overall exhaustion profile. Finally, the effect of TNFR2 on the overall anti-tumor response was established using TNFR2 KO mice and an antagonist.
    RESULTS: We reveal that upregulation of TNFR2 coincides with the gain of phenotypic markers and functions reflective of terminal exhaustion. Loss of TNFR2 affords a novel population of T cells that express TIM3 but possess diminished TOX levels and contain functional characteristics of both progenitor and terminally exhausted cells. TIM3+ TNFR2 KO T cells exhibit reduced exhaustion transcriptional programs and enhanced AP1 pathway signatures. Finally, TNFR2 KO mice demonstrate improved T cell-dependent control of tumor and chronic lymphocytic choriomeningitis (cLCMV) infection, while pharmacologic antagonism of TNFR2 licenses responses to checkpoint blockade in multiple subcutaneous and intracranial tumor models.
    CONCLUSIONS: Our data place TNFR2 signaling as a potential upstream regulator of TOX expression in T cells and propose TNFR2 antagonism as a novel immunotherapeutic strategy.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-3455
  6. iScience. 2025 Nov 21. 28(11): 113792
    Dysregulation of apolipoprotein o reprograms CCR7+CD4+T cell fate in primary autoimmune thrombocytopenia.
    Tengda Li, Xiang Li, He Huang.
      Primary immune thrombocytopenia involves antibody-driven platelet loss and perturbed CD4+ T cell regulation. By integrating single-cell transcriptomic, epigenetic, and functional analyses, we delineated CCR7+CD4+ T cell states with distinct metabolic and transcriptional programs. A subset enriched in patients exhibited reduced oxidative phosphorylation and enhanced glycolysis, accompanied by elevated expression of SP100 and its downstream transcriptional targets FOXP1 and CDK6. Trajectory analysis positioned these cells as developmentally arrested intermediates that, in normal individuals, mature into CCR7+ cells expressing apolipoprotein O (APOO). Functional perturbations revealed that APOO preserves oxidative metabolism and CCR7 identity while restraining SP100-dependent transcription. Methylation profiling identified APOO hypermethylation and transcriptional silencing in patient-derived CD4+ T cells. Together, these data define APOO as a metabolic-transcriptional checkpoint governing CCR7+CD4+ T cell fate, whose repression fosters dysfunctional differentiation and immune imbalance in autoimmune thrombocytopenia.
    Keywords:  hematology; immunology; transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.113792
  7. bioRxiv. 2025 Oct 05. pii: 2025.10.03.680201. [Epub ahead of print]
    Methionine regulates antitumor function of CD8 + T cells through polyamine synthesis.
    Tian Zhao, Gillian A Carleton, Sarah Macpherson, Madison Shiyuk, Joseph Monaghan, Jun Han, Oro Uchenunu, Robert Rottapel, Ralph J DeBerardinis, Kelly M Stewart, Bo-Hyun Kim, Juan Ausió, David R Goodlett, Helena Pětrošová, Kyle D Duncan, Julian J Lum.
      Methionine is an essential amino acid critical for T cell activation. While methionine restriction (MR) combined with immune checkpoint blockade has been shown to enhance T cell function, the impact of methionine on adoptive T cell therapies is largely unexplored. Here, we examined the functionality of T cells under MR and pharmaceutical inhibition of the methionine cycle (MAT2Ai), using primary T cells and a murine adoptive T cell therapy model. In vitro , transient MR or MAT2Ai treatment increased interferon gamma (IFNγ) expression in CD8 + T cells, whereas sustained MR led to the upregulation of T cell exhaustion-associated markers. Mechanistically, transient MR suppressed the polyamine synthesis pathway, and supplementation with polyamines reversed MR-induced IFNγ expression. Genetic ablation of s-adenosylmethionine decarboxylase, an enzyme in the polyamine synthesis pathway, recapitulated the effect of MR, indicating that transient MR enhances T cell function by inhibiting polyamine synthesis. Despite this, transient MR treatment of ovalbumin (OVA)-specific (OT-I) CD8 + T cells prior to adoptive transfer did not improve antitumor efficacy against EG7-OVA tumors in vivo . In contrast, sustained dietary MR accelerated EG7-OVA tumor growth in mice treated with OT-I T cells, demonstrating that methionine availability is essential for the activity of adoptively transferred T cells. These findings suggest that enhancing methionine availability in the tumor microenvironment may improve the efficacy of adoptive T cell therapies.
    DOI:  https://doi.org/10.1101/2025.10.03.680201
  8. Clin Rheumatol. 2025 Nov 20.
    High glucose-induced mitophagy accelerates premature aging of T cells in patients with rheumatoid arthritis.
    Jiaxin Lei, Yongao Wen, Lingyi Li, Huiyan Ji.
       OBJECTIVES: Premature T cell aging, marked by telomere shortening and cell cycle arrest, plays a key role in the pathogenesis of rheumatoid arthritis (RA). Growing evidence suggests that high glucose-induced metabolic dysfunction critically regulates both cellular aging and RA progression. This study explores how high glucose exacerbates T cell aging, providing novel insights into the mechanisms underlying RA development.
    METHODS: CD4+ T cells isolated from RA patients and healthy controls, along with HC-derived CD4+ T cells cultured in either low- or high-glucose conditions, were analyzed for aging markers including telomere length and cell cycle regulatory proteins to evaluate glucose-dependent effects. Cellular metabolism was characterized through: (1) glucose uptake (2-NBDG assay), (2) mitochondrial respiration (oxygen consumption rate analysis), and (3) mitophagy activity (DRP1/PINK1/parkin protein levels by immunoblotting). Mechanistic studies employed both pharmacological interventions (2-DG for glycolysis inhibition, succinyl phosphonate for OGDH inhibition, Mdivi-1 for DRP1 blockade) and genetic manipulation (DRP1 knockdown and overexpression) to delineate the roles of glucose metabolism and DRP1-mediated mitophagy in T cell aging.
    RESULTS: RA-derived CD4+ T cells exhibited increased glucose uptake and mitochondrial dysfunction. Enhanced mitophagy accelerated T-cell aging in RA. Mechanistically, high glucose promoted succinate accumulation, a key TCA cycle metabolite, leading to succinylation of Zinc Finger Protein 76 (ZNF76), a DRP1 transcription factor. This activated ZNF76, upregulating DRP1-mediated mitophagy and driving T-cell aging. Targeting glucose uptake and mitophagy may thus reverse T-cell dysfunction and ameliorate RA severity.
    CONCLUSION: Elevated mitophagy induced by high glucose represents a cell-autonomous mechanism driving premature T cell aging in RA, presenting a novel therapeutic avenue for disease management. Key Points • Dysregulated glucose metabolism is a key driver of T cell aging and RA pathogenesis. • High glucose exposure triggers metabolic reprogramming, leading to succinate accumulation. • Accumulated succinate induces ZNF76 succinylation and enhances DRP1-dependent mitophagy-a phenotype consistently observed in CD4+ T cells from RA patients. • DRP1-dependent mitophagy drives T cell aging in RA.
    Keywords:  CD4+ T cells; DRP1; Rheumatoid Arthritis; Succinylation
    DOI:  https://doi.org/10.1007/s10067-025-07815-z
  9. Metabolism. 2025 Nov 13. pii: S0026-0495(25)00307-5. [Epub ahead of print]175 156438
    Obesity rewires CD8+ T cell iron metabolism in adipose tissue to fuel metabolic inflammation.
    Jinfen Dai, Zixuan Zeng, Lishuan Wang, Wei Yuan, Karina Cunha E Rocha, Junho Park, Garam An, Ke Wang, Jisoo Song, Qian Xiang, Ying Duan, Chengjia Qian, Varsha Beldona, Whasun Lim, Enfu Hui, Michael Karin, Wei Ying.
      Sufficient nutrient supply is important for the maintenance of non-lymphoid tissue resident CD8+ T cell homeostasis, but the role of labile iron remains unclear. Here, we find adipose tissue CD8+ T cells exhibit elevated labile iron and mitochondrial Fe2+ compared to splenic counterparts, driving high ROS and IFNγ production. In obesity, an increase in Fe2+ influx into mitochondria enhances adipose tissue CD8+ cell functions, but weight loss normalizes CD8+ cell iron metabolism. Ncoa4 knockout reduces labile iron, blunting ROS and IFNγ production, while Fth1 knockout elevates Fe2+ and ROS, elevating IFNγ production. CD8+ cell-specific activation of NRF2 restores iron homeostasis by upregulating ferritin and promoting oxidative detoxification, suppressing adipose tissue CD8+ T cell accumulation and IFNγ production. Finally, NRF2 overexpression in CD8+ T cells attenuates obesity-related adipose tissue inflammation and metabolic disorders. These results highlight the crucial role of labile iron supply in adipose tissue CD8+ T cell homeostasis.
    Keywords:  Adipose tissue; CD8+ T cells; Insulin resistance; Iron metabolism; Obesity
    DOI:  https://doi.org/10.1016/j.metabol.2025.156438
  10. Nat Immunol. 2025 Nov 19.
    CD47 induces T cell exhaustion through interaction with thrombospondin-1.
      
    DOI:  https://doi.org/10.1038/s41590-025-02346-w
  11. Mol Immunol. 2025 Nov 20. pii: S0161-5890(25)00265-2. [Epub ahead of print]188 121-130
    Astragalus polysaccharide promotes CD8 + T cell activity by downregulating Tim-3 to potentiate antitumor immunity.
    Peijuan Liu, Shuang Wang, Yixiao Bin, Zhiqian Xin, Haijiao Yang, Tianjiao Zhang, Wangge Xie, Ke Wang, Wen Yin, Hai Zhang.
      It is well known that Astragalus polysaccharide (APS) exerts potent antitumor effects by enhancing T cell cytotoxicity via the PD-1/PD-L1 axis. However, whether APS can also modulate T cell activity via alternative checkpoint molecules remains unclear. Here, we addressed this question using complementary in vitro and in vivo approaches. In vitro, APS reduced the Tim-3 + cell population among human PBMCs. Further analysis revealed that APS specifically affected only the proportion of Tim-3 +CD8 + T cells. Along with the decreased proportion of Tim-3 + cells, CD8 + T cell immune activity was enhanced, as shown by increased expression of the early activation molecule CD69, increased secretion of GZMB, and enhanced capacity to kill human lung cancer cells. The results of transcriptome sequencing suggested that the APS-induced downregulation of Tim-3 might be related to the regulation of the transcription factor RORB. Experiments in an in vivo B16-F10 melanoma model revealed that APS enhanced T cell function by reducing the number of tumor-infiltrating Tim-3 + T cells, consequently suppressing tumor cell proliferation in mice. Collectively, our findings demonstrate that APS reduces the Tim-3 +CD8 + T cell population among PBMCs and enhances T cell cytotoxicity, providing a novel theoretical foundation for explaining the mechanism underlying APS immunomodulation.
    Keywords:  Astragalus polysaccharide; CD8 + T cells; Tim-3; immunomodulatory; tumor
    DOI:  https://doi.org/10.1016/j.molimm.2025.11.010
  12. bioRxiv. 2025 Sep 30. pii: 2025.09.28.679049. [Epub ahead of print]
    MDR1 promotes CD8 T cell persistence in tumors and protects against cytotoxic chemotherapy.
    Lincoln A Brown, Megan M Erwin, Natalie R Favret, Claudia N McDavid, Jessica J Roetman, Zachary D Ewell, Melissa M Wolf, Kristen A Murray, Jack E Smithwick, Marti A Goemann, Mary Philip.
      Multidrug transporters, including multidrug resistance-1 (MDR1), are recognized chiefly for effluxing chemotherapeutic drugs out of tumor cells. However, they are also expressed in many normal cells and tissues, including lymphocytes, but their physiological role is less well-understood. Here, we investigated the role of MDR1 in tumor-specific CD8 T cells (TST), which are critical in antitumor immunity and key targets of immunotherapies. Using a clinically-relevant genetic liver cancer mouse model, we investigated the efflux dynamics of TST as they underwent activation, proliferation, and differentiation to dysfunctional states in tumor-bearing hosts. Surprisingly, we found that late-stage/terminally dysfunctional TST had the highest efflux capacity in both murine and human liver tumors. TST upregulated transcription of Abcb1a, encoding MDR1. We used CRISPR/Cas9 to generate MDR1-deficient TST, which persisted poorly in tumor-bearing mice as compared to MDR1-sufficient TST. MDR1 expression improved TST viability and reduced reactive oxygen species accumulation. Loss of MDR1 made T cells more susceptible to cytotoxic chemotherapy-induced cell death. Our findings demonstrate a role for MDR1 in regulating TST persistence and oxidative stress, with implications for antitumor T cell therapies in patients and immune regulation following cytotoxic chemotherapy.
    Keywords:  ABCB1; chemotherapy; efflux; multidrug resistance 1; tumor-specific CD8 T cell
    DOI:  https://doi.org/10.1101/2025.09.28.679049
  13. Nat Metab. 2025 Nov 20.
    Hepatocyte mitochondrial NAD+ content is limiting for liver regeneration.
    Sarmistha Mukherjee, Ricardo A Velázquez Aponte, Caroline E Perry, Won Dong Lee, Kevin A Janssen, Marc Niere, Gabriel K Adzika, Mu-Jie Lu, Hsin-Ru Chan, Xiangyu Zou, Beishan Chen, Nicole Bye, Teresa Xiao, Jin-Seon Yook, Oniel Salik, David W Frederick, Ryan B Gaspar, Khanh V Doan, James G Davis, Joshua D Rabinowitz, Douglas C Wallace, Nathaniel W Snyder, Shingo Kajimura, Xiaolu A Cambronne, Mathias Ziegler, Joseph A Baur.
      Nicotinamide adenine dinucleotide (NAD+) precursor supplementation shows metabolic and functional benefits in rodent models of disease and is being explored as potential therapeutic strategy in humans. However, the wide range of processes that involve NAD+ in every cell and subcellular compartment make it difficult to narrow down the mechanisms of action. Here we show that the rate of liver regeneration is closely associated with the concentration of NAD+ in hepatocyte mitochondria. We find that the mitochondrial NAD+ concentration in hepatocytes of male mice is determined by the expression of the transporter SLC25A51 (MCART1). The heterozygous loss of SLC25A51 modestly decreases mitochondrial NAD+ content in multiple tissues and impairs liver regeneration, whereas the hepatocyte-specific overexpression of SLC25A51 is sufficient to enhance liver regeneration comparably to the effect of systemic NAD+ precursor supplements. This benefit is observed even though NAD+ levels are increased only in mitochondria. Thus, the hepatocyte mitochondrial NAD+ pool is a key determinant of the rate of liver regeneration.
    DOI:  https://doi.org/10.1038/s42255-025-01408-5
  14. Autoimmun Rev. 2025 Nov 15. pii: S1568-9972(25)00218-6. [Epub ahead of print] 103957
    Senescent CD4+ T cells and autoimmune diseases: Mechanisms and therapeutic prospects.
    Yue Hu, Liting He, Hai Long.
      Senescent CD4⁺ T cells exhibit classical features of T-cell senescence-including telomere attrition, reduced proliferative capacity, and an upregulated senescence-associated secretory phenotype (SASP)-while also displaying unique characteristics. Notably, they maintain relatively healthy mitochondrial mass compared with senescent CD8⁺ T cells, a distinction that influences their roles in immune regulation and tissue pathology. Multiple signaling pathways, such as the ATM-DDR-p53 axis, AMPK-TAB1-p38 cascade, mTOR signaling, mitochondrial-ROS axis, and IL-7/IL-2 cytokine networks, are dysregulated during the senescence of CD4⁺ T cells. Importantly, senescent CD4⁺ T cells can promote chronic inflammation, disrupt immune homeostasis, and remodel tissue microenvironments through the secretion of SASP components (e.g., IL-6, IL-8, TNF-α, and MMPs). They also have the potential to enhance antibody secretion by B cells, ultimately contributing to tissue-specific damage. These aberrant cells have been shown to accumulate in several autoimmune diseases (ADs), including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis (SSc). Targeting senescent CD4⁺ T cells with senotherapeutic agents and SASP inhibitors has been shown to markedly suppress AD progression, underscoring the translational potential of this therapeutic approach. However, more specific senescence markers are needed to accurately identify senescent CD4⁺ T cells. This review synthesizes current knowledge on senescent CD4⁺ T cells and their involvement in autoimmune diseases. Future research should prioritize elucidating their pathogenic mechanisms and developing targeted therapeutic strategies to mitigate their detrimental effects in ADs.
    Keywords:  Autoimmune diseases; CD4(+) T cell; Cell senescence; Rheumatoid arthritis; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.autrev.2025.103957
  15. Nature. 2025 Nov 19.
    Tumour-reactive heterotypic CD8 T cell clusters from clinical samples.
    Sofía Ibáñez-Molero, Johanna Veldman, Juan Simon Nieto, Joleen J H Traets, Austin George, Kelly Hoefakker, Anita Karomi, Rolf Harkes, Bram van den Broek, Su Min Pack, Liselotte Tas, Nils L Visser, Susan E van Hal-van Veen, Paula Alóndiga-Mérida, Maartje Alkemade, Iris M Seignette, Renaud Tissier, Marja Nieuwland, Martijn van Baalen, Joanna Poźniak, Erik Mul, Simon Tol, Sofia Stenqvist, Lisa M Nilsson, Jonas A Nilsson, John B A G Haanen, Winan J van Houdt, Daniel S Peeper.
      Emerging evidence suggests a correlation between CD8+ T cell-tumour cell proximity and anti-tumour immune response1,2. However, it remains unclear whether these cells exist as functional clusters that can be isolated from clinical samples. Here, using conventional and imaging flow cytometry, we show that from 21 out of 21 human melanoma metastases, we could isolate heterotypic clusters, comprising CD8+ T cells interacting with one or more tumour cells and/or antigen-presenting cells (APCs). Single-cell RNA-sequencing analysis revealed that T cells from clusters were enriched for gene signatures associated with tumour reactivity and exhaustion. Clustered T cells exhibited increased TCR clonality indicative of expansion, whereas TCR-matched T cells showed more exhaustion and co-modulation when conjugated to APCs than when conjugated to tumour cells. T cells that were expanded from clusters ex vivo exerted on average ninefold increased killing activity towards autologous melanomas, which was accompanied by enhanced cytokine production. After adoptive cell transfer into mice, T cells from clusters showed improved patient-derived melanoma control, which was associated with increased T cell infiltration and activation. Together, these results demonstrate that tumour-reactive CD8+ T cells are enriched in functional clusters with tumour cells and/or APCs and that they can be isolated and expanded from clinical samples. Typically excluded by single-cell gating in flow cytometry, these distinct heterotypic T cell clusters are a valuable source to decipher functional tumour-immune cell interactions and may also be therapeutically explored.
    DOI:  https://doi.org/10.1038/s41586-025-09754-w
  16. Trends Immunol. 2025 Nov 20. pii: S1471-4906(25)00269-8. [Epub ahead of print]
    Reframing IL-27: a central regulator of CD8+ T cell immunity.
    Valentina Venzin, Matteo Iannacone.
      Interleukin-27 (IL-27), a member of the IL-12 cytokine family, was long viewed primarily as a regulator of CD4+ T cell immunity. Subsequent studies revealed that IL-27 also directly modulates CD8+ T cells, displaying both stimulatory and inhibitory potential. Recent work extends this earlier literature, showing that IL-27 in infection and cancer can promote effector differentiation, sustain survival, and reverse dysfunction, often without the systemic toxicity associated with related cytokines. This review outlines the molecular features, signaling mechanisms, and cellular sources of IL-27, integrating emerging evidence from viral, tumor, and autoimmune settings. We propose that IL-27 operates not as an inherently pro- or anti-inflammatory cytokine but as a context-dependent tuner of CD8+ T cell cytotoxic immunity, offering new opportunities for therapeutic exploitation.
    Keywords:  CD8(+) T cell immunity; IL-27; T cell dysfunction; cytokine signaling; cytotoxic T lymphocytes; immunotherapy
    DOI:  https://doi.org/10.1016/j.it.2025.10.012
  17. Int Rev Immunol. 2025 Nov 17. 1-30
    Mitochondria in the immune system: Therapeutic potential from mitochondria transfer.
    Thao Hoang Nhu Le, Van Thi Tuong Nguyen.
      Mitochondria serve as the powerhouses of living cells, supplying energy and essential building blocks for cellular activities. The immune system exhibits a dynamic and active characteristic within the body, wherein immune cells are constantly activated and primed for pathogens without causing harmful effects on the self-body. These characteristics necessitate that immune cells function effectively and correctly, supported by a sufficient energy supply and metabolism from the mitochondria. Mitochondrial dysfunction leads to immune dysregulation, resulting in inappropriate inflammation, autoimmunity, immunodeficiency, and hypersensitive responses, all of which contribute to the development of illness and disease. Recent studies on mitochondrial transfer in immune cells indicate that mitochondrial replacement could emerge as a promising tool for rectifying immune cell function. This review will emphasize the role of mitochondria in various immune cell types and explore how mitochondrial dysfunction can result in pathogenesis in different conditions. We also discuss the potential application of mitochondrial transfer and transplantation to- and from immune cells in the context of health and disease.
    Keywords:  Immunology; immunometabolism; mesenchymal stem cells; metabolism; mitochondria transfer
    DOI:  https://doi.org/10.1080/08830185.2025.2577986
  18. J Exp Med. 2026 Feb 02. pii: e20250439. [Epub ahead of print]223(2):
    SLC7A8 is essential for metabolic fitness and function of Th2 cells.
    Santosh K Panda, Do-Hyun Kim, Pritesh Desai, Shitong Wu, Patrick Fernandes Rodrigues, Raki Sudan, Yizhou Liu, Haerin Jung, Intelly Lee, Susan Gilfillan, Marina Cella, Steven J Van Dyken, Marco Colonna.
      Amino acids are essential for the activation and function of CD4 T helper (Th) cells, which differentiate into Th1, Th2, Th17, and Treg subsets to coordinate immune responses. While specific amino acid transporters have been identified for Th1, Th17, and Tregs, a transporter regulating Th2 cells remains unknown. This study identifies SLC7A8 as a Th2-specific amino acid transporter in the Th compartment. We found that Slc7a8 expression is upregulated in Th2 cells compared with other T helper subsets, and Slc7a8 deficiency impairs Th2 cell proliferation and cytokine production. Furthermore, SLC7A8 was found to be crucial for an effective type 2 immune response to helminth infection and allergen-induced lung inflammation. Mechanistically, Slc7a8 deficiency disrupted Th2 cell metabolism, leading to reduced mTOR activation and, consequently, diminished mitochondrial function along with an impaired c-Myc pathway; these defects cumulatively induced cellular stress that curtailed cell growth and survival. Collectively, these findings highlight a previously unknown role for SLC7A8 in Th2 cells, with potential implications for understanding and treating type 2 immune-related diseases.
    DOI:  https://doi.org/10.1084/jem.20250439
  19. Nat Immunol. 2025 Nov 20.
    Author Correction: CD8+ T cells induce cachexia during chronic viral infection.
    Hatoon Baazim, Martina Schweiger, Michael Moschinger, Haifeng Xu, Thomas Scherer, Alexandra Popa, Suchira Gallage, Adnan Ali, Kseniya Khamina, Lindsay Kosack, Bojan Vilagos, Mark Smyth, Alexander Lercher, Joachim Friske, Doron Merkler, Alan Aderem, Thomas H Helbich, Mathias Heikenwälder, Philipp A Lang, Rudolf Zechner, Andreas Bergthaler.
      
    DOI:  https://doi.org/10.1038/s41590-025-02369-3
  20. Biochem Biophys Res Commun. 2025 Nov 12. pii: S0006-291X(25)01688-2. [Epub ahead of print]792 152972
    PTEN deficiency impairs IL-15-dependent T-cell immunity against prostate cancer.
    Yujie Xing, Zixuan Zeng, Chi Wang, Yuchen Qian, Zhuang Chen, Wenyue Huang, Mengxi Huan, Yalong Wang, Yang Gao.
      Prostate cancer (PCa) is widely recognized as an immunologically "cold" tumor that responds poorly to immunotherapy, largely due to its poorly infiltrated immune microenvironment. Genetic loss or functional inactivation of phosphatase and tensin homolog (PTEN) is a well-established driver of PCa tumorigenesis and progression. However, the mechanisms by which PTEN-deficiency shapes the tumor immune landscape, particularly T cell infiltration and activity, remain poorly understood. Here, we report that PTEN deficiency is associated with reduced T-cell infiltration in human PCa tissues. CRISPR/Cas9-mediated knockout (KO) of Pten in murine syngeneic tumor models similarly results in diminished intratumoral CD8+ T cell accumulation. Mechanistically, loss of PTEN suppresses IL-15 production by impairing activation of the cGAS-STING signaling pathway. Restoration of IL-15 in Pten KO PCa cells reinvigorates antitumor immunity and promotes T-cell infiltration within the tumor microenvironment. Together, our findings identify PTEN as a critical regulator of IL-15-associated T-cell immunity and suggest that IL-15-based therapeutic strategies may offer a promising approach for PTEN-deficient PCa.
    Keywords:  IL-15; Immune microenvironment; PTEN; Prostate cancer
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152972
This page is being maintained by Thomas Krichel. It was last updated on 2025‒11‒23 at 6:38.