bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–06–22
24 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells.
  2. CLNS1A regulates genome stability and cell cycle progression to control CD4 T cell function and autoimmunity.
  3. Targeting glutamine metabolism in CD4+ T-cell-mediated autoimmune diseases.
  4. Immunometabolism in systemic lupus erythematosus.
  5. Mitochondrial dysfunction in the regulation of aging and aging-related diseases.
  6. Immunogenomic characteristics and prognostic implications of terminally exhausted CD8+ T cells in colorectal cancers.
  7. Innovative approaches to CAR-T cell therapy: the role of lipid metabolism pathways.
  8. High expression of CCL3/CCL4/CCL5/CCR5 promotes exhausted CD8+ T cells terminal differentiation and is associated with poor prognosis in pediatric B-ALL patients.
  9. Tumor-Associated NK Cells Regulate Distinct CD8+ T-cell Differentiation Program in Cancer and Contribute to Resistance against Immune Checkpoint Blockers.
  10. IL-17 links the tumor suppressor LKB1 to gastrointestinal inflammation and polyposis.
  11. ENPP1 governs the metabolic regulation of effector T cells in autoimmunity by detecting cytosolic mitochondrial DNA.
  12. FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression.
  13. Two distinct subpopulations of human stem-like memory T cells exhibit complementary roles in self-renewal and clonal longevity.
  14. CARD11 signaling regulates CD8+ T cell tumoricidal function.
  15. SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging.
  16. To be similar, or not to be similar, that is the question: a story of CD8+ T cells in psoriatic arthritis.
  17. Id2 levels determine the development of effector vs. exhausted tissue-resident memory CD8+ T cells during CNS chronic infection.
  18. Anti-tumor CD8+ T cell responses are compromised in sickle cell disease.
  19. Single-cell analysis of temporal immune cell dynamics in alopecia areata reveals a causal role for clonally expanded CD8+ T cells in disease.
  20. Analysis of mitochondrial membrane potential, ROS, and calcium.
  21. NAD+ glycohydrolases-CD38 as a therapeutic target in aging: physiological roles, molecular mechanisms, and future opportunities in anti-aging research.
  22. Aging induces T cells with distinct transcriptomic profiles and functions in brain-associated tissues.
  23. Age-related changes in the proteome and mitochondrial metabolism of rabbit adipose-derived stromal/stem cells.
  24. Iron and the immune system.
  1. Nat Commun. 2025 Jun 20. 16(1): 5355
    Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells.
    Megan R Teh, Nancy Gudgeon, Joe N Frost, Linda V Sinclair, Alastair L Smith, Christopher L Millington, Barbara Kronsteiner, Jennie Roberts, Bryan P Marzullo, Hannah Murray, Alexandra E Preston, Victoria Stavrou, Jan Rehwinkel, Thomas A Milne, Daniel A Tennant, Susanna J Dunachie, Andrew E Armitage, Sarah Dimeloe, Hal Drakesmith.
      Iron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people and decreased iron availability impairs immunity. Nevertheless, how iron deprivation impacts immune cell function remains poorly characterised. We interrogate how physiologically low iron availability affects CD8+ T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation does not substantially alter initial post-activation increases in cell size and CD25 upregulation. However, low iron profoundly stalls proliferation (without influencing cell viability), alters histone methylation status, gene expression, and disrupts mitochondrial membrane potential. Glucose and glutamine metabolism in the TCA cycle is limited and partially reverses to a reductive trajectory. Previous studies identified mitochondria-derived aspartate as crucial for proliferation of transformed cells. Despite aberrant TCA cycling, aspartate is increased in stalled iron deficient CD8+ T cells but is not utilised for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Exogenous aspartate markedly rescues expansion and some functions of severely iron-deficient CD8+ T cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck, which is bypassed by supplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+ T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.
    DOI:  https://doi.org/10.1038/s41467-025-60204-7
  2. Sci Immunol. 2025 Jun 20. 10(108): eadq8860
    CLNS1A regulates genome stability and cell cycle progression to control CD4 T cell function and autoimmunity.
    Liwei Wang, Lucile Noyer, Miki Jishage, Yin-Hu Wang, Anthony Y Tao, Maxwell McDermott, Ivan Gando, Ikjot Sidhu, Ke Hu, Li Zhong, Katherine Sun, Dominik Drmic, Ulrike Kaufmann, Stefan Feske.
      Pathogenic CD4 T cells drive autoimmunity in diseases such as multiple sclerosis (MS) and inflammatory bowel disease (IBD). Through a forward genetic screen, we identified chloride nucleotide-sensitive channel 1A (CLNS1A) as a key regulator of inflammation in the experimental autoimmune encephalomyelitis (EAE) model of MS. CLNS1A is expressed in several subsets of CD4 T cells, including pathogenic T helper 17 (pTH17) cells. Deletion of Clns1a in T cells resulted in DNA damage, cell cycle arrest, impaired T cell proliferation, and effector function, thereby protecting mice from both EAE and IBD. We found that CLNS1A interacts with protein arginine methyl transferase 5 (PRMT5). Moreover, CLNS1A regulates symmetric histone dimethylation and the expression of genes involved in DNA repair, replication, and cell cycle progression. Thus, CLNS1A plays an important role in CD4 T cells by promoting genome stability and cell cycle progression.
    DOI:  https://doi.org/10.1126/sciimmunol.adq8860
  3. Immunol Cell Biol. 2025 Jun 18.
    Targeting glutamine metabolism in CD4+ T-cell-mediated autoimmune diseases.
    Zheng Li, ZeHong Su, ZhiMin Wu, LvHeng He, PingPing Hu, GaoJian Lian.
      CD4+ T cells play a vital role in the occurrence and development of autoimmune diseases (AID). The differentiation direction and function of CD4+ T cells are both regulated by metabolic reprogramming, which differs across various CD4+ T subsets. Glutamine (Gln), as an immunoregulatory nutrient, not only provides bioenergy and biosynthesis for the differentiation and effector function of CD4+ T cells but also regulates intracellular redox conditions and produces metabolic intermediates that are used for epigenetic modification of effector cell genes. Here, we review the metabolic characteristics of Gln in CD4+ T cells and its regulatory effects on CD4+ T-cell differentiation and function. We also summarize potential targets on Gln metabolism for AID therapy, including Gln transporters, Gls1, GSH synthesis and epigenetic modification. However, the primary challenge remains how to achieve cell type-specific metabolic inhibition in vivo. Therefore, future research should focus on developing selective and effective therapeutic agents that modulate Gln metabolism while minimizing cytotoxicity for AID treatment.
    Keywords:  autoimmune disease; epigenetic modification; glutamine; glutaminolysis; selective immunotherapy
    DOI:  https://doi.org/10.1111/imcb.70042
  4. Nat Rev Rheumatol. 2025 Jun 16.
    Immunometabolism in systemic lupus erythematosus.
    Eduardo Patiño-Martinez, Mariana J Kaplan.
      Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by chronic inflammation, tissue damage, accelerated cardiovascular disease and the synthesis of autoantibodies that target nucleic acids and nuclear protein complexes. Emerging evidence underscores the key role of immune metabolic dysregulation in SLE, revealing how metabolic reprogramming during immune cell activation influences disease development and progression. Alterations in key metabolic pathways such as glycolysis and oxidative phosphorylation profoundly affect the activation, differentiation and function of B and T cells, monocytes, neutrophils and other immune cells, driving inflammation and tissue injury. This Review synthesizes current findings on immune cell metabolism in animal models of lupus and in patients with SLE, highlighting the interplay of metabolic disturbances, mitochondrial dysfunction and disease pathogenesis. Furthermore, it explores the potential of targeting metabolic pathways as therapeutic strategies to mitigate organ damage and improve outcomes in SLE.
    DOI:  https://doi.org/10.1038/s41584-025-01267-0
  5. Cell Commun Signal. 2025 Jun 19. 23(1): 290
    Mitochondrial dysfunction in the regulation of aging and aging-related diseases.
    Xianhong Zhang, Yue Gao, Siyu Zhang, Yiqi Wang, Xinke Pei, Yufei Chen, Jinhui Zhang, Yichen Zhang, Yitian Du, Shauilin Hao, Yujiong Wang, Ting Ni.
      Aging is an irreversible physiological process that progresses with age, leading to structural disorders and dysfunctions of organs, thereby increasing the risk of chronic diseases such as neurodegenerative diseases, diabetes, hypertension, and cancer. Both organismal and cellular aging are accompanied by the accumulation of damaged organelles and macromolecules, which not only disrupt the metabolic homeostasis of the organism but also trigger the immune response required for physiological repair. Therefore, metabolic remodeling or chronic inflammation induced by damaged tissues, cells, or biomolecules is considered a critical biological factor in the organismal aging process. Notably, mitochondria are essential bioenergetic organelles that regulate both catabolism and anabolism and can respond to specific energy demands and growth repair needs. Additionally, mitochondrial components and metabolites can regulate cellular processes through damage-associated molecular patterns (DAMPs) and participate in inflammatory responses. Furthermore, the accumulation of prolonged, low-grade chronic inflammation can induce immune cell senescence and disrupt immune system function, thereby establishing a vicious cycle of mitochondrial dysfunction, inflammation, and senescence. In this review, we first outline the basic structure of mitochondria and their essential biological functions in cells. We then focus on the effects of mitochondrial metabolites, metabolic remodeling, chronic inflammation, and immune responsesthat are regulated by mitochondrial stress signaling in cellular senescence. Finally, we analyze the various inflammatory responses, metabolites, and the senescence-associated secretory phenotypes (SASP) mediated by mitochondrial dysfunction and their role in senescence-related diseases. Additionally, we analyze the crosstalk between mitochondrial dysfunction-mediated inflammation, metabolites, the SASP, and cellular senescence in age-related diseases. Finally, we propose potential strategies for targeting mitochondria to regulate metabolic remodeling or chronic inflammation through interventions such as dietary restriction or exercise, with the aim of delaying senescence. This reviewprovide a theoretical foundation for organismal antiaging strategies.
    Keywords:  Aging-related diseases; Cellular senescence; Chronic inflammation; Metabolic remodelling; Mitochondria
    DOI:  https://doi.org/10.1186/s12964-025-02308-7
  6. Front Immunol. 2025 ;16 1601188
    Immunogenomic characteristics and prognostic implications of terminally exhausted CD8+ T cells in colorectal cancers.
    Ji-Ae Lee, Hye Eun Park, Dae-Won Lee, Sae-Won Han, Tae-You Kim, Seung-Yong Jeong, Kyu Joo Park, Jeong Mo Bae, Gyeong Hoon Kang.
       Introduction: T-cell exhaustion is a major mechanism of immune evasion. Recently, the therapeutic and prognostic implications of progenitor exhausted T cells (Tpex) and terminally exhausted T cells (Ttex) have been explored in various cancer types. This study explored the immunogenomic characteristics and prognostic implications of Tpex and Ttex in colorectal cancers (CRCs).
    Methods: We performed multiplex immunofluorescence (mIF) using antibodies against CK, CD3, CD8, TCF1, and FOXP3 to assess diverse subsets of tumor-infiltrating lymphocytes (TILs) in 517 patients with stage III or high-risk stage II CRCs. We compared the infiltration level of these TIL subsets with the genetic profiles of CRCs, including microsatellite instability (MSI), tumor mutational burden (TMB), and mutations in 40 tumor-associated genes across five biological pathways.
    Results: CD8+ T cell density, the CD8/CD3 ratio, and the Ttex/CD8+ T cell ratio were elevated in microsatellite instability-high and tumor mutational burden-high tumors. Survival analysis showed that, higher CD8+ T cell density, higher regulatory T cell/CD3+ T cell ratio, and higher Ttex/CD8+ T cell ratio exhibited better 5-year relapse-free survival (RFS) rates. When tumors were categorized into CD8-high, CD8-low/Ttex-low, and CD8-low/Ttex-high groups, the CD8-high and CD8-low/Ttex-high groups showed better 5-year RFS than the CD8-low/Ttex-low group.
    Discussion: Ttex infiltration is associated with MSI and TMB status and may serve as a prognostic marker of CRCs.
    Keywords:  colorectal cancer; exhausted T cell; microsatellite instability; prognosis; tumor mutational burden
    DOI:  https://doi.org/10.3389/fimmu.2025.1601188
  7. J Transl Med. 2025 Jun 17. 23(1): 670
    Innovative approaches to CAR-T cell therapy: the role of lipid metabolism pathways.
    Minjie Guo, Yuting Zhang, Xiao Yuan, Xu Wang.
      The efficient response structure of chimeric antigen receptor T (CAR-T) cells has led to significant success in the treatment of hematological malignancies. However, when confronted with the challenges associated with solid tumors, CAR-T cells have increasingly exhibited limitations, including inadequate infiltration and a shortened lifespan. Consequently, enhancing CAR-T cells to broaden their applicability across a wider range of malignancies has emerged as an urgent priority. Nutrient metabolism is integral to the entire lifecycle of CAR-T cells, with lipid metabolism serving as a critical pathway for sustaining the energy supply of memory T cells. This aspect is essential for the long-term survival of CAR-T cells and underpins their overall efficacy. This article aims to explore the impact of tumors on T-cell lipid metabolism, drawing on existing research findings, and analyzing strategies for improving CAR-T cells from this perspective. It is hoped that this investigation will provide new insights for enhancing the efficacy of CAR-T cell therapies.
    Keywords:  CAR-T cell; Co-stimulatory domains; Cytokines; Lipid metabolism; T cell
    DOI:  https://doi.org/10.1186/s12967-025-06718-6
  8. Int J Immunopathol Pharmacol. 2025 Jan-Dec;39:39 3946320251346823
    High expression of CCL3/CCL4/CCL5/CCR5 promotes exhausted CD8+ T cells terminal differentiation and is associated with poor prognosis in pediatric B-ALL patients.
    Jiamian Zheng, Yupei Zhang, Xueting Peng, Cunte Chen, Jie Chen, Liye Zhong, Yangqiu Li, Songnan Sui.
      This study aims to identify differentially upregulated ligand-receptor interactions between B-ALL cells and exhausted CD8+ T cells and to develop a multivariate Cox regression model for predicting the overall survival of pediatric B-ALL patients based on CCL3/CCL4/CCL5 expression levels. Pediatric B cell-acute lymphoblastic leukemia (B-ALL) is a hematopoietic malignancy. T cell exhaustion has an important impact on the prognosis of leukemia. The interaction between tumor cells and T cells can influence the degree of T cell exhaustion. However, the effects of B-ALL cells on exhausted T cell subpopulations and how the interaction influences the prognosis of B-ALL patients remain unclear. Single-cell RNA sequencing (scRNA-Seq) data from pediatric B-ALL patients were downloaded from GEO. Cell interaction analysis identified ligand-receptor pairs between B-ALL cells and exhausted CD8+ T cell. To confirm the function of CCL3/CCL4/CCL5/CCR5 in prognosis prediction, quantitative real-time polymerase chain reaction (qRT-PCR) was employed. We further developed an innovative stratified model that integrates CCL3, CCL4, and CCL5 through multi-Cox regression. Clustering of scRNA-Seq data revealed an increased proportion of exhausted CD8+ T cells in relapsed B-ALL, especially terminal exhausted CD8+ T cells (CD8_Ex), with increased exhaustion and decreased proliferation scores. Moreover, the CCL3/CCL4/CCL5-CCR5 axis was upregulated in interactions between B-ALL cells and terminal CD8_Ex. Transcriptome data from 221 pediatric B-ALL samples revealed that high CCL3/CCL4/CCL5/CCR5 levels correlate with low overall survival (OS). A multivariate Cox regression model incorporating CCL3/CCL4/CCL5 predicted prognoses. Finally, a model based on the adult B-ALL patients from our center also accurately predicted prognoses. We report for the first time the crucial role of the CCL3/CCL4/CCL5-CCR5 axis in the differentiation of terminal exhausted CD8+ T cells in B-ALL. High expression of CCL3, CCL4, CCL5, and CCR5 correlates with poor prognosis in B-ALL, suggesting potential biomarkers and therapeutic targets.
    Keywords:  B cell-acute lymphoblastic leukemia; cell interaction; exhausted CD8+ T cells; prognosis
    DOI:  https://doi.org/10.1177/03946320251346823
  9. Cancer Discov. 2025 Jun 18. OF1-OF23
    Tumor-Associated NK Cells Regulate Distinct CD8+ T-cell Differentiation Program in Cancer and Contribute to Resistance against Immune Checkpoint Blockers.
    No-Joon Song, Juan Xie, Kyeong Joo Jung, Yi Wang, Joanna Pozniak, Niccolo Roda, Jean-Christophe Marine, Brian P Riesenberg, Hyeongseon Jeon, Anjun Ma, Nathanael Cox, Darren Wethington, Kelsi Reynolds, Tong Xiao, Anqi Li, Parker Kronen, Nicholas Denko, David P Carbone, Qin Ma, William E Carson, Bethany L Mundy-Bosse, Christin E Burd, Jayajit Das, Dongjun Chung, Zihai Li.
      Immune checkpoint blockers (ICB) targeting the PD-1/PD-L1 axis represent established therapies for many cancers. However, resistance occurs in most patients due to complex immune-suppressive mechanisms in the tumor microenvironment. NK cells can play effector roles in tumor control, but their impact on T-cell dysfunction and ICB efficacy remains controversial. Through genetic and antibody-mediated NK cell depletion, we found that a subset of tumor-associated NK cells plays a negative role in ICB sensitivity; they further impede CD8+ T-cell differentiation toward a CD69+ BCL2+ EOMES+ GZMB+ TIM3- GITR- phenotype. Mechanistically, the retinoic acid receptor α-dependent differentiation program in CD8+ T cells is hindered by tumor-infiltrating NK cells via competition for IFNα and IL-2. Finally, we observed that lower frequencies of NK cells correlate with better clinical responses to ICBs in patients with cancer. These findings suggest potential avenues for enhancing CD8+ T cell-centered immunotherapy by targeting regulatory NK cells.
    SIGNIFICANCE: Although NK cells are traditionally viewed as antitumor effectors, our study uncovers their unexpected suppressive role in CD8+ T cell-based immunotherapy. By competing for cytokines, they disrupt retinoic acid receptor α-driven CD8+ T-cell differentiation and limit ICB efficacy. Clinically, reduced NK cell presence is associated with an enhanced immunotherapy response. See related article by Pozniak et al. p. XX.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-1232
  10. Sci Adv. 2025 Jun 20. 11(25): eadt5933
    IL-17 links the tumor suppressor LKB1 to gastrointestinal inflammation and polyposis.
    Shelby E Compton, Lisa M DeCamp, Brandon M Oswald, Susan M Kitchen-Goosen, Kin H Lau, Robert Fillinger, Michael S Dahabieh, Alexandra Vander Ark, Connie M Krawczyk, Russell G Jones.
      Mutations in the tumor suppressor liver kinase B1 (LKB1) promote the development of gastrointestinal (GI) polyps of unknown etiology. Here, we identify IL-17 as a novel driver of LKB1-dependent polyp growth. GI tumors from mice bearing heterozygous mutations in Stk11 (which encodes LKB1) display signatures of pathogenic IL-17-producing CD4+ T helper 17 (TH17) cells. LKB1 constrains T cell inflammatory potential, as Stk11/LKB1 haploinsufficiency promotes T cell differentiation toward pathogenic IL-17-producing T cell lineages (CD4+ TH17 and CD8+ Tc17) in vitro and following intestinal infection. Mechanistically, aberrant CREB-regulated transcription coactivator 2 (CRTC2)-dependent signaling drives pathogenic TH17 cell programs downstream of LKB1 haploinsufficiency. Targeting this circuit via CRTC2 deletion or IL-17 blockade antagonizes GI polyp growth in mouse models of Peutz-Jeghers syndrome. These findings establish LKB1 as a gatekeeper of inflammatory type 3 (IL-17-dependent) T cell responses and identify a CRTC2-IL-17 signaling axis that can be targeted therapeutically to block the growth of LKB1 mutant GI tumors.
    DOI:  https://doi.org/10.1126/sciadv.adt5933
  11. Cell Rep. 2025 Jun 13. pii: S2211-1247(25)00622-9. [Epub ahead of print]44(6): 115851
    ENPP1 governs the metabolic regulation of effector T cells in autoimmunity by detecting cytosolic mitochondrial DNA.
    Huiyan Ji, Wanwan Jiang, Juan Zhang, Mengdi Liu, Danhua Su, Jiaxin Lei, Lingyi Li, Ming Zheng, Ting Liu, Zhichun Liu, Qinghua Cao, Lin Xu, Sidong Xiong, Zhenke Wen.
      T cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE), yet the underlying molecular mechanisms governing their fate remain elusive. Here, we identify cytosolic mitochondrial DNA (mtDNA) as an intrinsic trigger for driving effector T cell differentiation in patients with SLE. Specifically, accumulated cytosolic mtDNA is sensed by ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which enhances the transcription of GLUT1 and glycolysis in SLE T cells. This metabolic shift reduces lipogenesis and depletes free fatty acids (FFAs), impairing the N-myristylation and lysosomal localization of AMP-activated protein kinase (AMPK). Inactive AMPK fails to restrain mammalian target of rapamycin complex 1 (mTORC1), leading to its hyperactivation and driving the mal-differentiation of effector T cells. Consequently, interventions targeting ENPP1, glycolysis, AMPK, and mTORC1 effectively inhibit the generation of immunoglobulin (Ig)G anti-double-stranded DNA (dsDNA) and the progression of lupus nephritis in humanized SLE chimeras. Overall, our findings uncover an mtDNA-ENPP1-metabolic axis that governs effector T cell fate in autoimmunity.
    Keywords:  AMPK; CP: Immunology; CP: Molecular biology; ENPP1; SLE; T cell; mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.celrep.2025.115851
  12. Cell Metab. 2025 Jun 12. pii: S1550-4131(25)00267-0. [Epub ahead of print]
    FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression.
    Christy M Gliniak, Ruth Gordillo, Yun-Hee Youm, Qian Lin, Clair Crewe, Zhuzhen Zhang, Bianca C Field, Teppei Fujikawa, Megan Virostek, Shangang Zhao, Yi Zhu, Clifford J Rosen, Tamas L Horvath, Vishwa Deep Dixit, Philipp E Scherer.
      Approximately 35% of US adults over 65 are obese, highlighting the need for therapies targeting age-related metabolic issues. Fibroblast growth factor 21 (FGF21), a hormone mainly produced by the liver, improves metabolism and extends lifespan. To explore its effects without developmental confounders, we generated mice with adipocyte-specific FGF21 overexpression beginning in adulthood. When fed a high-fat diet, these mice lived up to 3.3 years, resisted weight gain, improved insulin sensitivity, and showed reduced liver steatosis. Aged transgenic mice also displayed lower levels of inflammatory immune cells and lipotoxic ceramides in visceral adipose tissue, benefits that occurred even in the absence of adiponectin, a hormone known to regulate ceramide breakdown. These results suggest that fat tissue is a central site for FGF21's beneficial effects and point to its potential for treating metabolic syndrome and age-related diseases by promoting a healthier metabolic profile under dietary stress and extending healthspan and lifespan.
    Keywords:  FGF21; adipocytes; adiponectin; adipose tissue; aging; ceramides; inflammation; insulin sensitivity; longevity; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.011
  13. PLoS Biol. 2025 Jun 20. 23(6): e3003179
    Two distinct subpopulations of human stem-like memory T cells exhibit complementary roles in self-renewal and clonal longevity.
    Danai Koftori, Charandeep Kaur, Laura Mora Bitria, Yan Zhang, Linda Hadcocks, Ada W C Yan, Piotr F Burzyński, Kristin Ladell, Daniel E Speiser, Katrina M Pollock, Derek Macallan, Becca Asquith.
      T stem cell-like memory cells (TSCM cells) are considered to be essential for the maintenance of immune memory. The TSCM population has been shown to have the key properties of a stem cell population: multipotency, self-renewal and clonal longevity. Here we show that no single population has all these stem cell properties, instead the properties are distributed. We show that the human TSCM population consists of two distinct cell subpopulations which can be distinguished by the level of their CD95 expression (CD95int and CD95hi). Crucially, using long-term in vivo labelling of human volunteers, we establish that these are distinct populations rather than transient states of the same population. These two subpopulations have different functional profiles ex vivo, different transcriptional patterns, and different tissue distributions. They also have significantly different TREC content indicating different division histories and we find that the frequency of CD95hi TSCM increases with age. Most importantly, CD95hi and CD95int TSCM cells also have very different dynamics in vivo with CD95hi cells showing considerably higher proliferation but significantly reduced clonal longevity compared with CD95int TSCM. While both TSCM subpopulations exhibit considerable multipotency, no single population of TSCM cells has both the properties of self-renewal and clonal longevity. Instead, the "stemness" of the TSCM population is generated by the complementary dynamic properties of the two subpopulations: CD95int TSCM which have the property of clonal longevity and CD95hi TSCM which have the properties of expansion and self-renewal. We suggest that together, these two populations function as a stem cell population.
    DOI:  https://doi.org/10.1371/journal.pbio.3003179
  14. Nat Immunol. 2025 Jun 18.
    CARD11 signaling regulates CD8+ T cell tumoricidal function.
    Yu Hu, Qifan Zhao, Yingquan Qin, Song Mei, Benyu Wang, Haoyue Zhou, Linli Han, Yi Zang, Liangjiao Yao, Zhe He, Yingyi Li, Hecheng Li, Peng Zhang, Yan Zhang, Michael J Lenardo, Wei Lu.
      Chronic stimulation in the tumor microenvironment can induce exhausted CD8+ T (Tex) cells that have limited tumoricidal activity. Here, we show an inverse correlation between signal strength and Tex cell differentiation by using patient-derived mutations in the T cell receptor (TCR)-signaling protein CARD11. Strong TCR signaling of the E134G mutant inhibits Tex cell differentiation and increases tumor growth. Conversely, reduced TCR signaling by the K215M mutant promotes Tex cell differentiation with better tumor control. These effects are a result of a restrained tumor-specific TCR clonal repertoire of Tex cells that reduces immunopathology but compromises tumoricidal activity. Mechanistically, CARD11 is a TCR signal-strength sensor, controlling the TCR repertoire of Tex cells by regulating the trafficking and homeostasis of the TCR complex. Expanding the TCR repertoire during Tex cell differentiation by fine-tuning the CARD11-mediated TCR signal strength reinvigorated antitumor function and indicates a strategy for improving cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-025-02192-w
  15. Mol Cell. 2025 Jun 19. pii: S1097-2765(25)00464-2. [Epub ahead of print]85(12): 2390-2408.e6
    SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging.
    Khoa A Tran, Michael Gilbert, Berta N Vazquez, Alessandro Ianni, Benjamin A Garcia, Alejandro Vaquero, Shelley L Berger.
      Sirtuin enzymes are deeply associated with senescence and aging. Sirtuin proteins are tightly regulated, but how their levels are governed during aging and how they elicit tissue-specific cellular changes are unclear. Here, we demonstrate that SIRT7 undergoes proteasomal degradation during senescence via targeting by the E3 ligase TRIP12. We identified the transcription factor nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) as an interactor of SIRT7 and found NUCKS1 recruitment onto chromatin during senescence mediated by SIRT7 loss, correlating with increased NUCKS1 acetylation. NUCKS1 depletion delayed senescence, leading to reduced inflammatory gene expression associated with transcription factors RELA and CEBPβ. In Sirt7 knockout and aged mouse livers, NUCKS1 was bound at the promoters and enhancers of age-related genes, and these regulatory regions gained accessibility during aging. Overall, our results uncover NUCKS1 as an interactor of SIRT7 and indicate that proteasomal loss of SIRT7 during senescence and liver aging promotes NUCKS1 acetylation and chromatin binding to induce metabolic and inflammatory genes.
    Keywords:  NUCKS1; SIRT7; acetylation; aging; post-translation modification; protein regulation; senescence; sirtuins
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.025
  16. Arthritis Rheumatol. 2025 Jun 16.
    To be similar, or not to be similar, that is the question: a story of CD8+ T cells in psoriatic arthritis.
    Lais Osmani, Insoo Kang.
      
    DOI:  https://doi.org/10.1002/art.43284
  17. Cell Rep. 2025 Jun 17. pii: S2211-1247(25)00632-1. [Epub ahead of print]44(6): 115861
    Id2 levels determine the development of effector vs. exhausted tissue-resident memory CD8+ T cells during CNS chronic infection.
    Aboubacar Sidiki K Coulibaly, Lucie Nozeran, Céline Thomann, Marine Alis, Emilie Bassot, Ali Hassan, Rémi Porte, Marcy Belloy, Nicolas Blanchard, Frederick Masson.
      Tissue-resident memory T cells (Trms) are essential for regional immunity in non-lymphoid tissues. Although single-cell transcriptomics have revealed Trm heterogeneity in various diseases, the molecular mechanisms behind this diversity are unclear. To investigate this, we performed single-cell transcriptomic analysis of brain CD8+ T cells from mice chronically infected with Toxoplasma gondii. This analysis revealed a heterogeneous expression of the transcriptional regulator Id2 in brain Trms, correlating with different functional states. Using mixed bone marrow chimeras, we found that Id2 deficiency in T cells caused parasite-specific Trms to develop an altered phenotype with diminished effector functions and reduced expression of the key tissue-retention molecules CD49a, CXCR6, and CD103. Furthermore, Id2 loss in brain-infiltrating CD8+ T cells led to the accumulation of exhausted PD1+Tox+CD8+ Trm cells, while Id2 overexpression repressed T cell exhaustion. Overall, our study shows that Id2 levels dictate the acquisition of effector vs. exhausted phenotypes in CD8+ Trms during chronic CNS infection.
    Keywords:  CD8 T cells; CNS; CP: Immunology; Id2; T cell exhaustion; Toxoplasma gondii; Trm; chronic infection; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115861
  18. Nat Cancer. 2025 Jun 20.
    Anti-tumor CD8+ T cell responses are compromised in sickle cell disease.
    Luca Danelli.
      
    DOI:  https://doi.org/10.1038/s43018-025-01013-1
  19. Cell Rep. 2025 Jun 17. pii: S2211-1247(25)00569-8. [Epub ahead of print]44(7): 115798
    Single-cell analysis of temporal immune cell dynamics in alopecia areata reveals a causal role for clonally expanded CD8+ T cells in disease.
    Zhenpeng Dai, Yuqian Chang, Eunice Y Lee, Valia P Leifer, Eddy Hsi Chun Wang, Rolando Perez-Lorenzo, Annemieke de Jong, Angela M Christiano.
      Alopecia areata (AA) is an immune-mediated hair loss disorder characterized by the infiltration of immune cells, including clonally expanded CD8+ T cells into lesional skin. To explore the link between CD8+ T cell clonality and disease pathogenicity, we conducted single-cell RNA and T cell receptor (TCR) sequencing in the C3H/HeJ mouse model of AA. We analyzed T cells derived from skin and skin-draining lymph nodes to capture both the end-organ and the site of antigen priming and found striking hyper-expansion of T cell clones associated with disease onset. Using the hyperexpanded CD8+ TCR sequences, we generated TCR retrogenic mice engineered to express a single clonotypic T cell population, applied CRISPR-Cas9 to engineer these TCR sequences within CD8+ T cells, and performed depletion experiments to demonstrate that expanded CD8+ T cell clones are sufficient to initiate disease, establishing a causal relationship between CD8+ T cell clonality and pathogenicity in disease.
    Keywords:  CP: Immunology; TCR retrogenic mice; alopecia areata; autoimmune disease; clonal T cell expansion; hair follicle; pathogenic CD8(+) T cells; targeted T cell depletion
    DOI:  https://doi.org/10.1016/j.celrep.2025.115798
  20. Mol Cells. 2025 Jun 12. pii: S1016-8478(25)00062-7. [Epub ahead of print] 100238
    Analysis of mitochondrial membrane potential, ROS, and calcium.
    Hye-Kyung Park, Byoung Heon Kang.
      Mitochondria play a central role in cellular energy metabolism and signaling, and their dysfunction is associated with a wide range of diseases. Therefore, assessing mitochondrial function is essential for understanding their role in various cellular processes and disease progression. Here, we describe the principles and methodologies for analyzing mitochondrial membrane potential, reactive oxygen species, and calcium levels using the fluorescent probes TMRM, MitoSOX, and Rhod-2AM, respectively. This work provides a practical guide for researchers investigating mitochondrial function under physiological and pathological conditions.
    Keywords:  Calcium; MitoSOX; Mitochondria; ROS; Rhod-2AM; TMRM; membrane potential
    DOI:  https://doi.org/10.1016/j.mocell.2025.100238
  21. Biochem Pharmacol. 2025 Jun 12. pii: S0006-2952(25)00315-6. [Epub ahead of print] 117050
    NAD+ glycohydrolases-CD38 as a therapeutic target in aging: physiological roles, molecular mechanisms, and future opportunities in anti-aging research.
    Jing-Yu Sun, Zhi-Fei Wang, Wen-Hui Xu, Jun Zhao.
      As individuals age, tissue homeostasis and functionality gradually deteriorate, leading to the occurrence and advancement of age-related illnesses. Nicotinamide adenine dinucleotide (NAD+) is essential for metabolism and cellular energy generation. The significance of maintaining adequate the levels of NAD+ within biological systems to ameliorate age-related tissue degeneration and prevent age-related illnesses in senescent animals is now widely recognized, emphasizing the importance of increasing NAD+ levels. Cluster of differentiation 38 (CD38), a multifunctional enzyme, plays a significant role in maintaining the cellular equilibrium of NAD+ through the consumption of NAD+. Recent research has shown a correlation between aging and upregulation of CD38 expression, potentially resulting in a reduction in NAD+ with increasing age. In contrast, the lack of CD38 has been shown to have a beneficial effect on slowing the aging process. Consequently, CD38 has been increasingly identified as a potential therapeutic target for interventions aimed at combatting aging. This study investigated the physiological roles of CD38, its ramifications in the aging process, possible molecular mechanisms associated with its involvement in aging-related diseases, and possible therapeutic applications of small-molecule inhibitors targeting CD38 in the context of aging. In this review, we provide a comprehensive analysis of the potential applications and future opportunities of CD38 in anti-aging research.
    Keywords:  Aging; Anti-aging regulatory target; CD38; CD38 small-molecule inhibitors; Nicotinamide adenine dinucleotide
    DOI:  https://doi.org/10.1016/j.bcp.2025.117050
  22. Front Immunol. 2025 ;16 1619196
    Aging induces T cells with distinct transcriptomic profiles and functions in brain-associated tissues.
    Youwen Si, Yuanyue Zhang, Qi Yang.
       Background: Aging is known to induce the emergence of distinct lymphocyte populations with unique molecular and functional characteristics. However, the impact of aging on the transcriptomes and functional activities of CD4 and CD8 T cells in non-lymphoid tissue remains poorly understood. Investigating aging-induced transcriptomic changes in tissue-infiltrating immune cells may provide insights into tissue homeostasis and malignancy in the aging context.
    Methods: Single-cell RNA sequencing (scRNA-seq) was performed to compare the cell subsets and transcriptomes of CD4+ and CD8+ T cells in brain-associated tissue, including the meninges and choroid plexus of young and aged mice. Flow cytometry was used to analyze aging-associated CD4+ T cells in the hippocampus. Depletion antibodies were employed to investigate the functional role of aging-associated T cells.
    Results: Aging induces a shift in the transcriptomes of CD4+ and CD8+ T cells in the meninges and choroid plexus toward an effector memory phenotype. In aged mice, T helper 2 (Th2) cells, regulatory T cells (Tregs), and distinct subsets of CD153-expressing CD4+ T cells accumulate in these brain-associated regions. Notably, CD153-expressing CD4+ T cells also infiltrate the hippocampus. Depletion of CD153+ cells using anti-CD153 antibodies leads to impaired cognitive function, suggesting a potential protective role for these cells in the aging brain.
    Conclusions: Aging alters the transcriptome of brain-associated CD4+ and CD8+ T cells. In particular, distinct CD153-expressing CD4+ T cells accumulate in the meninges and choroid plexus, and also infiltrate the hippocampus during aging. These cells may play a protective role in maintaining brain homeostasis.
    Keywords:  CD153; CD4; CD8; T cell; aging; cognitive function
    DOI:  https://doi.org/10.3389/fimmu.2025.1619196
  23. Sci Rep. 2025 Jun 20. 15(1): 20183
    Age-related changes in the proteome and mitochondrial metabolism of rabbit adipose-derived stromal/stem cells.
    Alicia Toto Nienguesso, Juliane-Susanne Jung, Marie Alfes, Maria Schindler, Luisa Täubert, Carla Schmidt, Anne Navarrete Santos.
      Adipose tissue is continuously regenerated by stromal mesenchymal stem cells throughout life. This study hypothesises that early age-related changes in the proteome and metabolic properties of subcutaneous (s) and visceral (v) adipose tissue-derived stromal/stem cells (ASCs) from young and old rabbits contribute to a loss of stem cell plasticity and function. To test this, the proteome and metabolic properties of ASCs from young and old rabbits were analysed using mass spectrometry-based label-free quantification and mitochondrial respiration measurements (Seahorse Mito Cell Stress Test). Both sASCs and vASCs from old rabbits exhibited comparable clusters of differentially expressed proteins. However, age-related changes were more pronounced in sASCs, suggesting that ageing affects ASCs differently depending on anatomical origin. In particular, a cluster of mitochondrial proteins in sASCs was differentially expressed with age, correlating with a shift in metabolic profile. The increase in mitochondrial respiration indicates that ageing ASCs lose their quiescent state and plasticity, leading to accelerated proliferation and differentiation. These proteomic findings were validated by Western Blot analysis, which confirmed the differential expression of key mitochondrial proteins. These results highlight the role of cellular origin in stem cell ageing and provide insights into the mechanisms underlying age-related stem cell dysfunction.
    DOI:  https://doi.org/10.1038/s41598-025-06030-9
  24. Nat Rev Immunol. 2025 Jun 16.
    Iron and the immune system.
    Joe N Frost, Hal Drakesmith.
      Iron is a cofactor for hundreds of enzymes and biochemical processes that support cellular metabolism across the kingdoms of life. Because of this, the host and pathogen compete for iron as a vital resource. Moreover, research has shown that iron acquisition and iron trafficking have substantial effects on the immune system. This is especially important because iron-related disorders - both deficiency and overload - are common worldwide. In this Review, we describe how immune cells acquire and use iron, which branches of the immune system are most affected by iron and how changes in iron availability can affect infectious diseases, autoinflammatory disorders and antitumour immunity. We also discuss key unanswered questions and potential therapeutic opportunities to manipulate immunity by controlling iron trafficking.
    DOI:  https://doi.org/10.1038/s41577-025-01193-y
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