bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–09–07
25 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. MiR-29a/b Suppresses CD8+ T Cell Effector Function and Intestinal Inflammation.
  2. Loss of the actin remodeling protein Flightless-1 impairs CD8 and regulatory T cell function.
  3. Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.
  4. Zeaxanthin augments CD8+ effector T cell function and immunotherapy efficacy.
  5. Immunosenescence in multiple sclerosis: New insights and clinical implications.
  6. Commentary: Immunogenomic characteristics and prognostic implications of terminally exhausted CD8+ T cells in colorectal cancers.
  7. Single-cell clonal lineage tracing identifies the transcriptional program controlling the cell fate decisions by neoantigen-specific CD8 + T cells.
  8. Testicular immunosenescence: a key player in age-related spermatogenic decline.
  9. Method to Study Metabolism in Lymphoid Cells using Chemistry to Measure Puromycin Incorporation by Flow Cytometry.
  10. Tumor-derived EBI3 promotes CD8+ T cell exhaustion via STAT4-IL-10/CCL5 in gastric cancer.
  11. Chronic ISG15 Exposure Accelerates CD8+ T-cell Dysfunction while Increasing PD-1 Blockade Sensitivity in Oral Squamous Cell Carcinoma.
  12. Regulatory KIR+CD8+ T cells in pregnancy.
  13. Newfound immune cell in mice hints at why inflammation spikes with old age.
  14. Reproducible single-cell annotation of programs underlying T cell subsets, activation states and functions.
  15. The Wnt-NAD+ axis in cancer, aging, and tissue regeneration.
  16. Biomimetic lymph node-like scaffolds for optimized CAR-T cell expansion and potentiated antitumor efficacy.
  17. Chronic antigen stimulation in melanoma induces T cell exhaustion and limits efficacy of T cell bispecific therapies.
  18. Th17 cell pathogenicity in autoimmune disease.
  19. A Targeting Senescence and Recycling Intracellular Nicotinamide Adenine Dinucleotide Strategy for Attenuation of Senescence-Associated Phenotypes.
  20. CD226 identifies effector CD8+ T cells during tuberculosis and costimulates recognition of Mycobacterium tuberculosis-infected macrophages.
  21. HIV-1 controllers possess a unique CD8+ T cell activation phenotype and loss of control is associated with increased expression of exhaustion markers.
  22. Protocol for the coculture of murine vaginal epithelial organoids and T cells to induce resident memory CD8 T cell differentiation.
  23. Reproducible annotation of T cell subsets and activation states with gene expression programs.
  24. Efficient and Traceless Aptamer-Based Serial Selection of Naïve and Early Memory CD8 T Cells for CAR T Cell Therapy.
  25. Astragalin inhibits hepatitis B virus through functional reconstitution of CD8+ T cells and a direct effect on HBV control.
  1. Exploration (Beijing). 2025 Aug;5(4): 20240363
    MiR-29a/b Suppresses CD8+ T Cell Effector Function and Intestinal Inflammation.
    Yingying Lin, Yuqi Wang, Yuning Zhang, Yao Lu, Juan Chen, Yongting Luo, Jian He, Qingfeng Luo, Heng Quan, Weiru Yu, Yujia Luo, Peng Xue, Yi Xue, Xiaoya Lin, Rui Ding, Lining Chen, Yiran Wang, Zenghui Xia, Liang Zhao, Hao Zhang, Ran Wang, Qingyu Wang, Xifan Wang, Jiaqi Su, Fazheng Ren, Cong Lv, Yixuan Li, Huiyuan Guo.
      The role of CD8+ T cells in the pathogenesis of ulcerative colitis (UC) remains unclear. Similarly, the posttranscriptional regulation of the highly heterogenic CD8+ T cell populations and their effector function in IBD also remains poorly understood. Here, we find that miR-29a and -29b (miR-29a/b) regulate T cell fate, and their expression is higher near damaged colon tissue in patients with IBD compared to controls. In mice, we find that miR-29a/b suppresses the differentiation of CD8+ T cells and the secretion of pro-inflammatory and chemotactic factors during severe colitis by inhibiting transcriptional pathways, including those involving the T cell receptor and JAK-STAT signaling. Furthermore, we identify Ifng, an inflammatory factor that drives immune response and the reshaping of CD8+ T cell fate, as a potential target of the miRNAs. Finally, we show that delivery of miR-29 mimics to the colon of mice is sufficient to alleviate DSS-induced inflammation. Together, these data show that miR-29 plays an important role in suppressing T cell overactivation during inflammatory diseases.
    Keywords:  CD8+ T cell; Ifng‐JAK‐STAT; differentiation; miR‐29a/b; ulcerative colitis
    DOI:  https://doi.org/10.1002/EXP.20240363
  2. bioRxiv. 2025 Aug 20. pii: 2025.08.15.669900. [Epub ahead of print]
    Loss of the actin remodeling protein Flightless-1 impairs CD8 and regulatory T cell function.
    Michelle M Lissner, Jenna M Sullivan, Minjian Ni, McKenna Sherve, Anne M Hocking, Jessica A Hamerman, Daniel J Campbell.
      T cell immunity depends on the precise coordination of signaling networks with actin cytoskeleton remodeling, yet the molecular regulators of these processes remain incompletely defined. Flightless-1 (FLII) is a gelsolin-family actin regulator with unique leucine-rich repeats that can couple cytoskeletal dynamics to diverse signaling pathways. Here, using conditional knockout mice, we identify essential roles for FLII in both CD8⁺ and regulatory T cells. Loss of FLII in CD8⁺ T cells caused a profound loss of naive cells from the spleen, impaired CCR7-dependent migration, and defective accumulation in the lung parenchyma during antigen-specific responses to respiratory vesicular stomatitis virus infection, despite largely preserved activation, effector differentiation, and cytotoxic function. FLII-deficient Foxp3⁺ regulatory T cells maintained normal numbers but exhibited diminished CD25 expression, defective IL-2 signaling, and failed to restrain spontaneous, tissue-specific autoimmunity. These findings identify FLII as a critical and previously unrecognized orchestrator of T cell trafficking and immune regulation, which may link chemokine receptor signaling to actin remodeling and is essential for proper T cell migration and function.
    Keywords:  CD8+ T cells; Flightless-1; Gelsolin; Regulatory T cells
    DOI:  https://doi.org/10.1101/2025.08.15.669900
  3. EMBO Rep. 2025 Aug 29.
    Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.
    Lin Luo, Ana Victoria Lechuga-Vieco, Clara Sattentau, Mariana Borsa, Anna Katharina Simon.
      Dysfunctional mitochondria are a hallmark of T cell ageing and contribute to organismal ageing. This arises from the accumulation of reactive oxygen species (ROS), impaired mitochondrial dynamics, and inefficient removal of dysfunctional mitochondria. Both cell-intrinsic and cell-extrinsic mechanisms for removing mitochondria and their byproducts have been identified in T cells. In this review, we explore how T cells manage mitochondrial damage through changes in mitochondrial metabolism, mitophagy, asymmetric mitochondrial inheritance, and mitochondrial transfer, highlighting the impact of these mechanisms on T cell ageing and overall organismal ageing. We also discuss current therapeutic strategies aimed at removing dysfunctional mitochondria and their byproducts and propose potential new therapeutic targets that may reverse immune ageing or organismal ageing.
    Keywords:  Asymmetric Cell Division; Mitochondrial Metabolism; Mitochondrial Transfer; Mitophagy; T Cell Ageing
    DOI:  https://doi.org/10.1038/s44319-025-00536-z
  4. Cell Rep Med. 2025 Aug 28. pii: S2666-3791(25)00397-0. [Epub ahead of print] 102324
    Zeaxanthin augments CD8+ effector T cell function and immunotherapy efficacy.
    Freya Q Zhang, Jiacheng Li, Rukang Zhang, Jiayi Tu, Zhicheng Xie, Takemasa Tsuji, Hardik Shah, Matthew O Ross, Ruitu Lyu, Junko Matsuzaki, Anna Tabor, Kelly Xue, Fatima Choudhry, Chunzhao Yin, Hamed R Youshanlouei, Syed Shah, Michael W Drazer, Yu-Ying He, B Marc Bissonnette, Yuancheng Li, Hui Mao, Jun Huang, Lei Dong, Rui Su, Chuan He, Kunle Odunsi, Jing Chen, Hao Fan.
      The detailed mechanisms underlying the regulatory significance of dietary components in modulating anti-tumor immunity remain largely unknown. Here, we apply a co-culture-based screening approach using a blood nutrient compound library and identify zeaxanthin (ZEA), a dietary carotenoid pigment found in many fruits and vegetables and known for its role in eye health, as an immunomodulator that enhances the cytotoxicity of CD8+ T cells against tumor cells. Oral supplementation with ZEA, but not its structural isomer lutein (LUT), enhances anti-tumor immunity in vivo. Integrated multi-omics mechanistic studies reveal that ZEA promotes T cell receptor (TCR) stimulation on the CD8+ T cell surface, leading to improved intracellular TCR signaling for effector T cell function. Hence, ZEA treatment augments the efficacy of anti-PD1 immune checkpoint inhibitor in vivo and the cytotoxicity of human TCR gene-engineered CD8+ T cells in vitro. Our findings uncover a previously unknown immunoregulatory function of ZEA, which has translational potential as a dietary element in bolstering immunotherapy.
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102324
  5. Mult Scler. 2025 Sep 02. 13524585251367611
    Immunosenescence in multiple sclerosis: New insights and clinical implications.
    Alice Laroni, Tiziana Vigo, Matilde Inglese, Antonio Uccelli.
      Aging is associated with profound changes in cellular function (senescence) and affects various tissues and systems, including the immune system (immunosenescence). Despite the increasing average age of individuals with multiple sclerosis (MS), little is known about what happens to the immune system of aging people with MS or about the impact of immunomodulatory and immunosuppressive treatments for MS on the aging immune system. In this topical review, we discuss the concepts of physiological cellular senescence and immunosenescence, and we review the latest available data on immunosenescence in MS. We examine evidence suggesting premature aging of the immune system in MS, including premature aging of T cells, reduced numbers of naïve lymphocytes, expansion of proinflammatory CD28- T cells, and the acquisition of an "aged" phenotype of CD8+ T cells in younger MS patients. Finally, we explore the clinical implications of immunosenescence on the efficacy and safety of disease-modifying therapies and propose drug candidates that could be tested in aged MS patients.
    Keywords:  Multiple sclerosis; aging; immunosenescence; inflammaging
    DOI:  https://doi.org/10.1177/13524585251367611
  6. Front Immunol. 2025 ;16 1654000
    Commentary: Immunogenomic characteristics and prognostic implications of terminally exhausted CD8+ T cells in colorectal cancers.
    Wenjiang Wu, Yingjie Liu, Peishan Yu, Linchong Yu.
      
    Keywords:  CD8+T cell exhaustion; CRC (colorectal cancer); ICD (immunogenic cell death); sample bias; spatial biology
    DOI:  https://doi.org/10.3389/fimmu.2025.1654000
  7. bioRxiv. 2025 Aug 18. pii: 2025.08.13.670223. [Epub ahead of print]
    Single-cell clonal lineage tracing identifies the transcriptional program controlling the cell fate decisions by neoantigen-specific CD8 + T cells.
    Ying Luo, Chen Yao, Tuoqi Wu.
      Neoantigen-specific T cells specifically recognize tumor cells and are critical for cancer immunotherapies. However, the transcriptional program controlling the cell fate decisions by neoantigen-specific T cells is incompletely understood. Here, using joint single-cell transcriptome and TCR profiling, we mapped the clonal expansion and differentiation of neoantigen-specific CD8 + T cells in the tumor and draining lymph node in mouse prostate cancer. Compared to other antitumor CD8 + T cells and bystanders, neoantigen-specific CD8 + tumor-infiltrating lymphocytes (TILs) upregulated gene signatures of T cell activation and exhaustion. In the tumor draining lymph node, we identified TCF1 + TOX - T SCM , TCF1 + TOX + T PEX , and TCF1 - TOX + effector-like T EX subsets among neoantigen-specific CD8 + T cells. Clonal tracing analysis of neoantigen-specific CD8 + T cells revealed greater clonal expansion in divergent clones and less expansion in clones biased towards T EX, T PEX , or T SCM . The T PEX subset had greater clonal diversity and likely represented the root of neoantigen-specific CD8 + T cell differentiation, whereas highly clonally expanded effector-like T EX cells were positioned at the branch point where neoantigen-specific clones exited the lymph node and differentiated into T EX TILs. Notably, T SCM differentiation of neoantigen-specific CD8 + clones in the lymph node negatively correlated with exhaustion and clonal expansion of the same clones in the tumor. In addition, the gene signature of neoantigen-specific clones biased toward tumor infiltration relative to lymph node residence predicted a poorer response to immune checkpoint inhibitor. Together, we identified the transcriptional program that controls the cell fate choices by neoantigen-specific CD8 + T cells and correlates with clinical outcomes in cancer patients.
    DOI:  https://doi.org/10.1101/2025.08.13.670223
  8. Front Cell Dev Biol. 2025 ;13 1669826
    Testicular immunosenescence: a key player in age-related spermatogenic decline.
    Ming-Wei Zhan, Mu-Hua Zhou, Bin-Bin Zhao, Xiao-Jie Bao, Yibo Chen, Jingyu Zhu.
      As global populations age, testicular aging has become a key contributor to the gradual decline in male fertility, characterized by lower sperm count, poorer sperm quality, and reduced reproductive potential. While the testis is traditionally viewed as an immune-privileged site, growing evidence shows that this immune protection weakens over time-a process now known as testicular immunosenescence. This review provides a comprehensive overview of age-related changes in the testicular immune landscape. These include the depletion of CD4+ and CD8+ T cells, dysfunction of regulatory T cells (Tregs), abnormal polarization of macrophages, and the breakdown of the blood-testis barrier (BTB). Together, these changes lead to chronic low-grade inflammation and disrupt the delicate environment required for healthy sperm production. In addition, we explore how immune aging is closely linked to metabolic changes, especially within Sertoli and Leydig cells. These intertwined processes form a feedback loop-an "immune-metabolic axis"-that accelerates germ cell death and impairs spermatogenesis. We also discuss emerging treatment strategies, such as anti-inflammatory therapies, mitochondrial support, and NAD+ precursor supplementation, which may help preserve testicular function and male fertility with age. By framing testicular immunosenescence as both a driving mechanism and a potential therapeutic target, this review opens up new directions for tackling age-related male reproductive decline.
    Keywords:  aging; blood-testis barrier (BTB); immune-metabolic axis; spermatogenic dysfunction; testicular immunosenescence
    DOI:  https://doi.org/10.3389/fcell.2025.1669826
  9. J Vis Exp. 2025 Aug 15.
    Method to Study Metabolism in Lymphoid Cells using Chemistry to Measure Puromycin Incorporation by Flow Cytometry.
    Zenia Kaul, Hirofumi Shibata, Pamela L Schwartzberg.
      Upon antigen stimulation, naïve T cells undergo rapid proliferation and expansion to effector T cells. Metabolism plays an important role in the generation of biomass needed for these rapidly proliferating cells and for the generation of molecules required for effector T cell differentiation and function, which influence the outcome of the adaptive immune response in infection or cancers. Naïve T cells reprogram their metabolism upon antigenic stimulation to increase the generation of ATP, which is required to support their growth, biosynthesis, and effector functions. ATP can be generated in a cell either by the mitochondrial-oxidative phosphorylation (OXPHOS) pathway or by the glycolytic pathway. Because most of the ATP generated in a dividing, growing cell is used up for the synthesis of proteins, protein synthesis has been used as a surrogate for ATP levels. Protein synthesis can be measured by the incorporation of puromycin, which mimics the 3' adenosine of a tRNA charged with a modified tyrosine and leads to spontaneous termination of protein translation. Metabolic inhibitors like 2-deoxyglucose (2DG), which blocks the glycolytic pathway, and Oligomycin (O), which blocks complex 5 of the electron transport chain (ETC), can be used to study the dependencies of cellular ATP generation on these two pathways in conjunction with evaluation of protein synthesis in a method called SCENITH. We describe here a variation of this method that detects puromycin incorporation by flow cytometry using chemistry. This method of studying metabolism is relatively easy and can be used for evaluating rare cell populations, as well as patient samples, by flow cytometry.
    DOI:  https://doi.org/10.3791/67377
  10. Cancer Immunol Res. 2025 Sep 01.
    Tumor-derived EBI3 promotes CD8+ T cell exhaustion via STAT4-IL-10/CCL5 in gastric cancer.
    Yong-Jia Yan, Xin Liu, Daohan Wang, Zexuan Shen, Wenxin Zhang, Zhaoxiong Zhang, Yangpu Jia, Peiyao Wang, Yuman Fong, Yanghee Woo, Weihua Fu.
      Combination chemotherapy and immunotherapy are effective against advanced gastric cancer (GC). However, T cell exhaustion in the tumor microenvironment may decrease the immune response and compromise the effectiveness of immunotherapy. Herein, we report the potential role of EBI3 in promoting T cell exhaustion and its mechanism in GC, showing high expression of EBI3 in GC. Correlation analysis between EBI3 expression level and clinical-pathological features indicated significant associations with Tumor stage, Nodal staging, pathologic stage, and degree of tumor differentiation. EBI3 expression levels correlated with a state of high CD8+ T cell exhaustion, as identified by transcriptome sequencing and mice orthotopic GC models. On exposure to EBI3, CD8+ T cells showed signs of cell exhaustion as reduced cytokine secretion and increased expression of inhibitory receptors in vitro/vivo studies. Mechanistically, EBI3 induced T cell exhaustion by promoting phosphorylation of STAT4, upregulating the transcription of downstream target genes CCL5 and IL-10. An anti-EBI3 heptapeptide (Val-Tyr-Leu-His-Trp-His-Asp) was developed, which competitively bound EBI3 and reversed the induction of T cell exhaustion. Taken together, we identified a T cell exhaustion mechanism in GC via the EBI3-STAT4-IL10/CCL5 axis and developed an anti-EBI3 heptapeptide with an antagonistic function. These findings provide a potential immunotherapeutic target and support the development of EBI3-based interventions to enhance immunotherapy efficacy in GC.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-24-1228
  11. Cancer Immunol Res. 2025 Aug 29.
    Chronic ISG15 Exposure Accelerates CD8+ T-cell Dysfunction while Increasing PD-1 Blockade Sensitivity in Oral Squamous Cell Carcinoma.
    Yu-Lin Chen, Amir Yousif, Chung-Hsing Chen, Ava Lowin, Abbey A Saadey, Ssu-Han Wang, Shih Sheng Jiang, Ya-Wen Chen, Hazem E Ghoneim.
      Immunotherapy has emerged as a promising treatment for head and neck squamous cell carcinoma (HNSCC), yet clinical responses remain limited. Elevated expression of interferon-stimulated gene 15 (ISG15), commonly observed in oral squamous cell carcinoma (OSCC), may contribute to this limited efficacy. Although chronic interferon signaling is known to impair CD8+ T cell function, the specific role of secreted ISG15 in T cell exhaustion remains unclear. Analysis of human OSCC datasets revealed significant enrichment of the ISG core score-including ISG15-in tumors compared to adjacent non-tumor tissues. Using a novel in vitro model of human T cell dysfunction, we found that acute ISG15 exposure enhances CD8+ T cell effector functions, whereas prolonged exposure induces severe dysfunction via a CD11a/LFA-1-independent, endocytosis-dependent mechanism. In an immunocompetent orthotopic OSCC model, ISG15-expressing tumors exhibited accelerated growth and recruited more tumor-reactive CD8+ T cells; however, these cells were functionally impaired. Importantly, PD-1 blockade treatment significantly slowed tumor progression and restored T cell function in ISG15-expressing tumors. Together, our findings reveal that chronic ISG15 exposure promotes CD8+ T cell dysfunction, but these cells remain responsive to PD-1 blockade. This study identifies ISG15 as a potential biomarker for identifying patients likely to benefit from PD-1 blockade therapy.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-0047
  12. Nat Rev Immunol. 2025 Sep 01.
    Regulatory KIR+CD8+ T cells in pregnancy.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-025-01225-7
  13. Nature. 2025 Sep 04.
    Newfound immune cell in mice hints at why inflammation spikes with old age.
    Gemma Conroy.
      
    Keywords:  Ageing; Immunology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-025-02788-0
  14. Nat Methods. 2025 Sep 03.
    Reproducible single-cell annotation of programs underlying T cell subsets, activation states and functions.
    Dylan Kotliar, Michelle Curtis, Ryan Agnew, Kathryn Weinand, Aparna Nathan, Yuriy Baglaenko, Kamil Slowikowski, Yu Zhao, Pardis C Sabeti, Deepak A Rao, Soumya Raychaudhuri.
      T cells recognize antigens and induce specialized gene expression programs (GEPs), enabling functions like proliferation, cytotoxicity and cytokine production. Traditionally, different T cell classes are thought to exhibit mutually exclusive responses, including TH1, TH2 and TH17 programs. However, single-cell RNA sequencing has revealed a continuum of T cell states without clearly distinct subsets, necessitating new analytical frameworks. Here, we introduce T-CellAnnoTator (TCAT), a pipeline that improves T cell characterization by simultaneously quantifying predefined GEPs capturing activation states and cellular subsets. Analyzing 1,700,000 T cells from 700 individuals spanning 38 tissues and five disease contexts, we identify 46 reproducible GEPs reflecting core T cell functions including proliferation, cytotoxicity, exhaustion and effector states. We experimentally demonstrate new activation programs and apply TCAT to characterize activation GEPs that predict immune checkpoint inhibitor response across multiple tumor types. Our software package starCAT generalizes this framework, enabling reproducible annotation in other cell types and tissues.
    DOI:  https://doi.org/10.1038/s41592-025-02793-1
  15. Trends Cell Biol. 2025 Aug 29. pii: S0962-8924(25)00172-2. [Epub ahead of print]
    The Wnt-NAD+ axis in cancer, aging, and tissue regeneration.
    Jilian Lamprecht, Sundos Abu Sanad, Anjali P Kusumbe, Shukry J Habib.
      The intricate interplay between Wnt signaling and nicotinamide adenine dinucleotide (NAD+) biosynthesis has emerged as a crucial axis that influences aging and tissue regeneration. Wnt signaling, a key regulator of cellular proliferation, differentiation, and tissue homeostasis, intersects with NAD+ metabolism, a cornerstone of cellular energy balance and genomic stability. This relationship is mediated through shared regulatory pathways involving sirtuins, poly(ADP-ribose) polymerases (PARPs), and metabolic enzymes which are sensitive to cellular NAD+ levels. Dysregulation of either pathway is implicated in cancer, age-related decline, and impaired regenerative capacity. This review consolidates current knowledge of the Wnt-NAD+ axis and highlights its cooperative roles in maintaining tissue integrity and combating the effects of aging. Furthermore, it explores therapeutic approaches targeting this axis to restore tissue health and enhance the capacity for repair, thereby offering promising avenues for addressing age-associated pathologies.
    Keywords:  age-associated pathologies; metabolic/developmental signaling integration; rejuvenation; stem cells; therapeutic targeting; tissue maintenance and repair
    DOI:  https://doi.org/10.1016/j.tcb.2025.07.006
  16. J Mater Chem B. 2025 Aug 28.
    Biomimetic lymph node-like scaffolds for optimized CAR-T cell expansion and potentiated antitumor efficacy.
    Huajin Zhang, Fujun Liu, Junyilang Zhao, Yong Wang, Yuge Shen, Qiqi Li, Hui Luo, Yu Chen, Rong Li, Fan Zhu, Shuo Xie, Yinhao Wei, Xupeng Gou, Danling Hu, Zhengji Li, Hanshuo Yang.
      Chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable promise in treating hematological malignancies. However, the ex vivo expansion of CAR-T cells is time-consuming, potentially impairing CAR-T cell function. Physiologically, T cell activation and proliferation occur within the lymph node (LN) paracortex, a dynamic environment structured by a three-dimensional (3D) reticular network (RN) that promotes cell migration and mediator delivery. Mimicking this physiological niche offers a compelling strategy to improve CAR-T cell expansion. Inspired by the structure of the RN, we developed a biomimetic RN-like poriferous microsphere (PM) to establish a 3D culture platform optimized for both T cell and CAR-T cell proliferation. This engineered system not only significantly enhanced the proliferation rates of human T cells and CAR-T cells compared to conventional methods, but also preserved a higher proportion of central memory T cells (TCM) and reduced the expression of exhaustion markers (PD-1, TIM-3, and LAG-3). Moreover, CAR-T cells expanded in PMs exhibited superior anti-tumor efficacy in both ex vivo and in vivo models, which correlated with the enrichment of pathways associated with robust T cell function at the RNA level. Overall, this biomimetic platform addresses critical limitations in human T/CAR-T cell expansion, preserving cell function and improving therapeutic outcomes.
    DOI:  https://doi.org/10.1039/d5tb01594d
  17. Oncoimmunology. 2025 Dec;14(1): 2526444
    Chronic antigen stimulation in melanoma induces T cell exhaustion and limits efficacy of T cell bispecific therapies.
    Idil Hutter-Karakoc, Eleni Maria Varypataki, Aparna Neelakandhan, Simone Lang, Vesna Kramar, Ahmet Varol, Sasha Simons, Marine Richard, Mudita Pincha, Dario Venetz, Johannes Sam, Nicole Joller, Christian Münz, Pablo Umana, Christian Klein, Maria Amann.
      T cell bispecific antibodies (TCBs) have demonstrated promising results in patients with solid tumors, yet the immunological mechanisms influencing their efficacy require further investigation. T cell exhaustion, induced by prolonged antigen exposure, is known to compromise T cell-based immunotherapies, but its effect on TCB efficacy remains unclear. Herein, we assessed the TCB efficacy on tumor-specific T cells, emphasizing their functional status. Utilizing an immunocompetent mouse model with melanoma expressing an immunogenic antigen, we showed that tumor-specific T cells acquire an exhausted phenotype and fail to expand under TCB treatment. Both mouse and human tumor-specific T cells in vitro demonstrated that chronically stimulated T cells exhibit a reduced response to TCBs. The comparison of TCB efficacy in T cell-inflamed versus non-inflamed tumors in mice revealed TCB success depends more on T cell functional fitness than their initial abundance. These data underscore the importance of T cell exhaustion, suggesting that exhausted tumor-specific T cells are unlikely to be the primary effectors redirected by TCBs for tumor eradication. Our study highlights the need to maintain T cell fitness and prevent exhaustion to enhance TCB therapy outcomes, which may help identify patients who could benefit most from TCB treatments in clinics.
    Keywords:  Cancer immunotherapy; T cell bispecific antibodies; T cell engagers; T cell exhaustion; antigen-specific T cells; chronic antigen stimulation; melanoma; solid tumors
    DOI:  https://doi.org/10.1080/2162402X.2025.2526444
  18. Exp Mol Med. 2025 Sep 01.
    Th17 cell pathogenicity in autoimmune disease.
    Eunchong Park, Maria Ciofani.
      T helper 17 (Th17) cells have been implicated in numerous inflammatory autoimmune diseases. Clinical benefits from targeting Th17 cell-related cytokines, such as IL-17 and IL-23, highlight how knowledge of Th17 cell development and effector function can be translated into treatments for inflammatory disease. Here we discuss the pathogenic roles of Th17 cells in autoimmune diseases such as multiple sclerosis, inflammatory bowel disease and psoriasis, with emphasis on the cytokines, transcriptional regulators and metabolites that influence Th17 cell differentiation and pathogenicity. Moreover, we address how intestinal environments and physiological responses affect Th17 cells in autoimmune diseases. We also examine current and emerging therapeutic strategies aimed at regulating Th17 cell-driven inflammation to mitigate autoimmune diseases.
    DOI:  https://doi.org/10.1038/s12276-025-01535-9
  19. ACS Nano. 2025 Sep 05.
    A Targeting Senescence and Recycling Intracellular Nicotinamide Adenine Dinucleotide Strategy for Attenuation of Senescence-Associated Phenotypes.
    Jian Liu, Mingjie Rong, Chen Liu, Lehui Lu.
      Cellular senescence is a critical factor in organismal aging and age-related diseases. Nicotinamide adenine dinucleotide (NAD+) has been shown to be closely related to the cellular senescence process and holds potential as a senotherapeutic agent. However, its clinical application has been hindered by challenges such as its inability to be directly absorbed by cells, instability, and lack of targeting specificity. To address these issues, a senescent cell targeting and intracellular NAD+ recycling strategy for attenuation of senescence-associated phenotypes has been developed. As a proof of concept, we demonstrate that the Cu-NAD@CM system can target and recognize senescent cells while restoring the NADH to NAD+ cycle and inhibiting senescence-associated secretory phenotype (SASP) expression. Our study reveals the significant therapeutic potential of the Cu-NAD@CM system in managing atherosclerosis (a disease involving multiple senescent cell types) and in doxorubicin-induced and d-galactose-induced senescent mouse models.
    Keywords:  age-related diseases; cellular senescence; macrophage membrane target; nicotinamide adenine dinucleotide; senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1021/acsnano.5c05124
  20. Cell Rep. 2025 Aug 29. pii: S2211-1247(25)00955-6. [Epub ahead of print]44(9): 116184
    CD226 identifies effector CD8+ T cells during tuberculosis and costimulates recognition of Mycobacterium tuberculosis-infected macrophages.
    Tomoyo Shinkawa, Evelyn Chang, Tasfia Rakib, Kelly Cavallo, Rocky Lai, Samuel M Behar.
      CD8+ T cells defend against Mycobacterium tuberculosis (Mtb) infection but variably recognize Mtb-infected macrophages. To investigate how chronic infection affects the diversity of lung parenchymal CD8+ T cells, we perform single-cell RNA sequencing (scRNA-seq) on cells from C57BL/6J mice infected for 6 and 41 weeks. We identify an effector lineage, including a cluster that expresses high levels of cytotoxic effectors and cytokines, and a dysfunctional lineage that transcriptionally resembles exhausted T cells. The most significantly differentially expressed gene between two distinct CD8+ T cell lineages is Cd226. Mtb-infected interferon (IFN)γ-enhanced yellow fluorescent protein (EYFP) reporter mice reveal that IFNγ production is enriched in CD226+CD8+ T cells, confirming these as functional T cells in vivo. Purified CD226+ but not CD226- CD8+ T cells recognize Mtb-infected macrophages, and CD226 blockade inhibits IFNγ and granzyme B production. Thus, efficient CD8+ T cell recognition of Mtb-infected macrophages requires CD226 costimulation, and CD226 expression identifies CD8+ T cells that recognize Mtb-infected macrophages.
    Keywords:  CD226; CD8 T cells; CP: Immunology; CP: Microbiology; adaptive immunity; antigen presentation; exhaustion; in vivo; infection; lung; mouse models; mycobacterium tuberculosis
    DOI:  https://doi.org/10.1016/j.celrep.2025.116184
  21. PLoS One. 2025 ;20(8): e0328706
    HIV-1 controllers possess a unique CD8+ T cell activation phenotype and loss of control is associated with increased expression of exhaustion markers.
    Amber D Jones, Zachary Capriotti, Erin Santos, Angel Lin, Rachel Van Duyne, Stephen Smith, Zachary Klase.
       BACKGROUND: HIV-1 controllers are a rare population of individuals that exhibit spontaneous control of HIV-1 infection without antiretroviral therapy. Understanding the mechanisms by which HIV-1 controllers maintain and eventually lose this ability would be highly valuable in HIV-1 cure or vaccine research. Previous work revealed the ability of CD8+ T cells isolated from HIV-1 controllers to suppress HIV-1 replication in matched CD4+ T cells and PBMCs ex vivo and suggested the loss of control may be tied to CD8+ T cell exhaustion.
    RESULTS: We explored whether CD8+ T cell exhaustion plays a role in the maintenance and loss of control by examining immune characteristics of HIV-1 persistent controllers and transient controllers who lost control within the duration of the study. Using flow cytometry, we analyzed exhaustion marker expression on CD8+ T cells from HIV-1 controllers and determined that they maintain a unique exhaustion profile as compared to people without HIV-1 and HIV-1 standard progressors. The low level of T cell exhaustion seen in HIV-1 controllers was reversed when these individuals lost control and showed increased viral loads. Combinatorial immune checkpoint blockade targeting exhaustion markers was able to restore ex vivo control in CD8+ T cells from former controllers.
    CONCLUSIONS: These results suggest that CD8+ T cell exhaustion compromises the ability to control viral replication in HIV-1 controllers. The character of exhaustion in response to HIV-1 and therapy is distinct in HIV-1 persistent controllers, transient controllers and standard progressors.
    DOI:  https://doi.org/10.1371/journal.pone.0328706
  22. STAR Protoc. 2025 Aug 29. pii: S2666-1667(25)00460-5. [Epub ahead of print]6(3): 104054
    Protocol for the coculture of murine vaginal epithelial organoids and T cells to induce resident memory CD8 T cell differentiation.
    Julian C Ramprashad, Ying Lin, Lalit K Beura.
      Inducing robust resident memory T cell (TRM) establishment in mucosal tissues could enhance immunotherapy and vaccine efficacy. However, the factors influencing TRM formation are not fully understood. We present a protocol to coculture murine effector CD8 T cells with epithelial organoids, which serve as a reductionist model for investigating TRM differentiation in vitro. We describe steps for naive CD8 T cell activation, coculture of T cells with vaginal epithelial organoids (VEOs), and analysis of T cell phenotypes via flow cytometry. For complete details on the use and execution of this protocol, please refer to Ulibarri et al.1.
    Keywords:  Cell culture; Immunology; Organoids; Tissue Engineering
    DOI:  https://doi.org/10.1016/j.xpro.2025.104054
  23. Nat Methods. 2025 Sep 03.
    Reproducible annotation of T cell subsets and activation states with gene expression programs.
      
    DOI:  https://doi.org/10.1038/s41592-025-02792-2
  24. Adv Healthc Mater. 2025 Aug 29. e02930
    Efficient and Traceless Aptamer-Based Serial Selection of Naïve and Early Memory CD8 T Cells for CAR T Cell Therapy.
    Abe Y Wu, Emmeline L Cheng, Nataly Kacherovsky, Abigail Marking, Arie Lin-Goldstein, Clinton M Heinze, Stephen J Salipante, Michael C Jensen, Suzie H Pun.
      Chimeric antigen receptor (CAR) T cell therapies have shown clinical success in cancer treatment. However, the compositions of the final products can differ substantially between patients, leading to variable treatment responses. Recent studies suggest that CAR T cells manufactured from defined T cell subsets show greater potency and persistence and improved predictability of therapeutic efficacy. Current clinical-scale selection of T cell subsets relies on antibody-based magnetic activated cell sorting, which is costly and results in suboptimal product purity and yield, presenting a significant challenge for clinical translation. Here, a high-affinity CD62L aptamer and a traceless, sequential selection system are reported for the high-yield and high-purity isolation of CD62L⁺CD8⁺ T cells without residual selection labels. It is demonstrated that multiple aptamer-reversal agent pairs can be integrated into a magnetic platform for multi-parameter and high-throughput cell sorting. CAR T cells manufactured from aptamer-selected CD62L⁺CD8⁺ T cells, encompassing naïve and early memory CD8+ T cells, exhibit distinct phenotypic and functional advantages compared to those manufactured from bulk CD8+ T cells. This aptamer-based approach has the potential to improve the clinical efficacy of current adoptive T cell therapies by enabling precise and scalable selection of T cell subsets, with broad applications beyond T cell subset selection.
    Keywords:  CAR T cells; CD62L; aptamers; cell isolation; immunology
    DOI:  https://doi.org/10.1002/adhm.202502930
  25. Eur J Pharmacol. 2025 Aug 29. pii: S0014-2999(25)00862-3. [Epub ahead of print]1005 178108
    Astragalin inhibits hepatitis B virus through functional reconstitution of CD8+ T cells and a direct effect on HBV control.
    Haohao Li, Shasha Yang, Huajun Zhao, Jian Zhang, Wei Guo, Tao Shen, Qiuju Han.
      Persistent HBV infection promotes hepatic lipid accumulation, a feature linked to immune dysfunction. We found cytotoxic T lymphocytes (CD8+ T cells) from chronic HBV infection (CHB) patients exhibited elevated lipid peroxidation in response to hepatic lipids accumulation. And lipid peroxidation drives CD8+ T cell dysfunction. Astragalin (AG), a natural active compound from Chinese herbs, reduced lipid peroxidation. Mechanically, AG upregulated Glutathione peroxidase 4 (GPX4) expression, protecting CD8+ T cells against membrane lipid peroxidation and reversing their exhaustion during chronic HBV infection. Importantly, AG significantly reduced circulating serum HBsAg and HBV DNA levels in HBV-carrier mice. Furthermore, AG directly reduced HBsAg, HBeAg and HBV RNA levels in HepG2.2.15 cells and significantly induced expression of the interferon-inducible antiviral protein myxovirus resistance protein A (MxA). In conclusion, AG exhibits dual anti-HBV activity by enhancing CD8+ T cell antiviral function and directly suppressing HBV replication, holding promise as a potential candidate for the treatment of chronic HBV infection.
    Keywords:  Astragalin; Chronic hepatitis B; Cytotoxic T lymphocytes; Glutathione peroxidase 4; Lipid peroxidation
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178108
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