bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–03–02
nineteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Notch dependent chromatin remodeling enables Gata3 binding and drives lineage specific CD8+ T cell function.
  2. Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells.
  3. Lymph nodes link sex-biased immune aging to compromised antigen recognition.
  4. Calcium signaling is essential for T helper 1 cell differentiation.
  5. Polymersome-mediated Cbl-b silencing activates T cells against solid tumors.
  6. Presetting CAR-T cells during ex vivo bio-manufacturing.
  7. Cancer ATF4-mediated CD58 endocytosis impairs anti-tumor immunity and immunotherapy.
  8. Publisher Correction: The glucose transporter 2 regulates CD8+ T cell function via environment sensing.
  9. Effector T cells under hypoxia have an altered transcriptome similar to tumor-stressed T cells found in non-responsive melanoma patients.
  10. Metabolic Regulation by p53: Implications for Cancer Therapy.
  11. Association of peripheral CD8+ T cell activation with disease activity and treatment resistance in systemic lupus erythematosus.
  12. CK2B Induces CD8+ T-Cell Exhaustion through HDAC8-Mediated Epigenetic Reprogramming to Limit the Efficacy of Anti-PD-1 Therapy in Non-Small-Cell Lung Cancer.
  13. Functional memory T cells are derived from exhausted clones and expanded by checkpoint blockade.
  14. Autophagy repression in effector T lymphocytes redefines paradigms in T cell biology.
  15. Single cell analysis identifies distinct CD4 + T cells associated with the pathobiology of pediatric obesity related asthma.
  16. Dietary cysteine enhances intestinal stemness via CD8 + T cell-derived IL-22.
  17. Mimicking the TCR immune synapse for improved CAR-T cell function.
  18. Glycolytic reprogramming shapes the histone acetylation profile of activated CD4+ T cells in juvenile idiopathic arthritis.
  19. CD301b+ dendritic cell-derived IL-2 dictates CD4+ T helper cell differentiation.
  1. Immunol Cell Biol. 2025 Feb 26.
    Notch dependent chromatin remodeling enables Gata3 binding and drives lineage specific CD8+ T cell function.
    Jessie O'Hara, Pushkar Dakle, Michelle Ly Thai Nguyen, Adele Barugahare, Taylah J Bennett, Vibha Av Udupa, Nicholas Murray, Gemma Schlegel, Constantine Kapouleas, Jasmine Li, Stephen J Turner, Brendan E Russ.
      Activation of CD8+ T cells enable them to control virus infections and tumors. This process involves the differentiation of naïve CD8+ T cells into effector and memory states, driven by specific transcription factors (TFs). Previously, we have shown that Granzyme A (Gzma) induction in activated CD8+ T cells depends on Gata3 and the establishment of a permissive chromatin landscape at the Gzma locus. Interestingly, Gzma expression is independent of IL-4 signaling, which typically upregulates Gata3 in CD4+ T cells, suggesting an alternative pathway for Gata3 induction. Here we demonstrate that Notch signals during CD8+ T cell activation promote Gzma expression. Inhibition of Notch signaling or loss of the Notch transactivator Rbp-j leads to reduced Gzma expression, with transcriptionally repressive chromatin at the Gzma locus. The genome targets of Gata3 differ in effector CD8+ T cells activated with IL-4 compared with those activated with Notch signals or isolated after IAV infection. This indicates that the signals received during CD8+ T cell activation can alter the chromatin landscape, affecting Gata3 function. Furthermore, Gata3 deficiency results in reduced IAV-specific CD8+ T cell responses and decreased Gzma expression, although the Gzma locus maintains a permissive chromatin landscape. These findings suggest that Notch signals received by virus-specific CD8+ T cells prepare the chromatin landscape for Gata3 binding to CD8+ lineage-specific gene loci, promoting effective CD8+ T cell immunity.
    Keywords:  CD8+ T cell; Gata3; Granzyme; Notch; T cell memory; influenza A virus
    DOI:  https://doi.org/10.1111/imcb.70002
  2. Nat Immunol. 2025 Feb 27.
    Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells.
    Linda V Sinclair, Tom Youdale, Laura Spinelli, Milica Gakovic, Alistair J Langlands, Shalini Pathak, Andrew J M Howden, Ian G Ganley, Doreen A Cantrell.
      Autophagy shapes CD8 T cell fate; yet the timing, triggers and targets of this process are poorly defined. Herein, we show that naive CD8 T cells have high autophagic flux, and we identify an autophagy checkpoint whereby antigen receptor engagement and inflammatory cytokines acutely repress autophagy by regulating amino acid transporter expression and intracellular amino acid delivery. Activated T cells with high levels of amino acid transporters have low autophagic flux in amino-acid-replete conditions but rapidly reinduce autophagy when amino acids are restricted. A census of proteins degraded and fueled by autophagy shows how autophagy shapes CD8 T cell proteomes. In cytotoxic T cells, dominant autophagy substrates include cytolytic effector molecules, and amino acid and glucose transporters. In naive T cells, mitophagy dominates and selective mitochondrial pruning supports the expression of molecules that coordinate T cell migration and survival. Autophagy thus differentially prunes naive and effector T cell proteomes and is dynamically repressed by antigen receptors and inflammatory cytokines to shape T cell differentiation.
    DOI:  https://doi.org/10.1038/s41590-025-02090-1
  3. bioRxiv. 2025 Feb 15. pii: 2025.02.11.637693. [Epub ahead of print]
    Lymph nodes link sex-biased immune aging to compromised antigen recognition.
    Lutz Menzel, Maria Zschummel, Meghan J O'Melia, Hengbo Zhou, Pin-Ji Lei, Lingshan Liu, Debattama R Sen, Lance L Munn, Timothy P Padera.
      A diverse naive CD8 T cell repertoire is essential to provide broad protection against infection and cancer. Aging diminishes naive T cells, reducing potential diversity and leading to lymph node contraction. Here, we revealed that this decline occurs earlier in males, resulting in significant sex differences in immunity during middle age. Earlier in life, naive CD8 T cells in males become virtual memory cells prone to premature senescence. Due to androgen-driven thymic atrophy in males, naïve CD8 T cells are insufficiently replenished. Therapeutic thymus rejuvenation via testosterone ablation restored naive CD8 T cells in lymph nodes of middle-aged male mice, leading to enhanced tumor recognition. These findings show the crucial role of sex and age on lymph node T cell repertoires and suggest potential strategies to restore immune function in males during aging.
    DOI:  https://doi.org/10.1101/2025.02.11.637693
  4. Nat Immunol. 2025 Feb 25.
    Calcium signaling is essential for T helper 1 cell differentiation.
      
    DOI:  https://doi.org/10.1038/s41590-025-02101-1
  5. Biomater Sci. 2025 Feb 28.
    Polymersome-mediated Cbl-b silencing activates T cells against solid tumors.
    Guanhong Cui, Yu Shao, Junyao Wang, Congcong Xu, Jinping Zhang, Zhiyuan Zhong.
      Unleashing T cell function is critical for efficacious cancer immunotherapy. Here, we present an in vivo T cell activation strategy by silencing Casitas B-lineage lymphoma proto-oncogene b (Cbl-b), an intracellular checkpoint, to effectively combat solid tumors. The polymersomes are able to efficiently load and deliver siRNA against cblb to T cells both in vitro and in vivo, successfully silencing the cblb gene expression in primary T cells and enhancing the IL-2 receptor CD25 expression, which in turn enhances T cell function and prevents T cell exhaustion. In vitro and in vivo studies showed that siRNA against cblb caused an effective inhibition of tumor progression in subcutaneous B16-F10 and LLC models, in which a significant increase of effector T cells in peripheral blood mononuclear cells and an increase of effector T cells and a significant decrease of Treg cells in the tumor were clearly observed. This polymersome-mediated down-regulation of the cblb gene in T cells provides a promising approach for activating T cells and enhancing their anti-tumor capacity.
    DOI:  https://doi.org/10.1039/d5bm00001g
  6. Mol Ther. 2025 Feb 22. pii: S1525-0016(25)00122-4. [Epub ahead of print]
    Presetting CAR-T cells during ex vivo bio-manufacturing.
    Xu Wang, Ying Liao, Dan Liu, Junnian Zheng, Ming Shi.
      Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. However, it continues to encounter significant obstacles, including treatment relapse and limited efficacy in solid tumors. While effector T cells exhibit robust cytotoxicity, central memory T cells and stem cell-like T cells are essential for in vivo expansion, long-term survival, and persistence. Strategies such as genetic engineering to enhance CAR-T cell efficacy and durability are often accompanied by increased safety risks, which not only raise regulatory approval thresholds but also escalate CAR-T production costs. In contrast, optimizing ex vivo manufacturing conditions represents a more straightforward and practical approach, offering the potential for rapid application to commercially approved CAR-T products and enhancement of their clinical outcomes. This review examines several factors that have been shown to improve T cell memory phenotype and in vivo cytotoxic activity, including cytokines, electrolytes, signaling pathway inhibitors, metabolic modulators, and epigenetic agents. The insights provided will guide the optimization of CAR-T cell industrial production. Furthermore, considerations for selecting appropriate conditions are discussed, balancing effectiveness, cost-efficiency, safety, and regulatory compliance, while addressing current challenges in the field.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.02.031
  7. J Transl Med. 2025 Feb 25. 23(1): 225
    Cancer ATF4-mediated CD58 endocytosis impairs anti-tumor immunity and immunotherapy.
    Hanyi Zeng, Jiaping Yu, Haijian Wang, Mengying Shen, Xuejing Zou, Ziyong Zhang, Li Liu.
      Co-stimulatory molecules are imperative for CD8+ T cells to eliminate target cell and maintain sustained cytotoxicity. Despite an advanced understanding of the co-stimulatory molecules deficiency that results in tumor escape, the tumor cell-intrinsic mechanisms that regulate co-stimulatory molecules remain enigmatic, and an in-depth dissection could facilitate the improvement of treatment options. To this end, in this study, we report that the deficiency of the critical costimulatory molecule CD58, mediated by the expression of ATF4 in tumor cells, impairs the formation of immunological synapses (IS) and leads to the deterioration of antitumor immune function of CD8+ T cells. Mechanistically, ATF4 transcriptionally upregulated dynamin 1 (DNM1) expression leading to DNM1-dependent endocytosis (DDE)-mediated degradation of CD58. Furthermore, administration of DDE inhibitor prochlorperazine or ATF4 knockdown effectively restored CD58 expression, boosting CD8+ T cell cytotoxicity and immunotherapy efficiency. Thus, our study reveals that ATF4 in tumor cells weakens CD58 expression to interfere with complete IS formation, and indicates potential approaches to improve the cytolytic function of CD8+ T cell in tumor immunotherapy.
    DOI:  https://doi.org/10.1186/s12967-025-06245-4
  8. Nat Metab. 2025 Feb 25.
    Publisher Correction: The glucose transporter 2 regulates CD8+ T cell function via environment sensing.
    Hongmei Fu, Juho Vuononvirta, Silvia Fanti, Fabrizia Bonacina, Antonio D'Amati, Guosu Wang, Thanushiyan Poobalasingam, Maria Fankhaenel, Davide Lucchesi, Rachel Coleby, David Tarussio, Bernard Thorens, Robert J Hearnden, M Paula Longhi, Paul Grevitt, Madeeha H Sheikh, Egle Solito, Susana A Godinho, Michele Bombardieri, David M Smith, Dianne Cooper, Asif J Iqbal, Jeffrey C Rathmell, Samuel Schaefer, Valle Morales, Katiuscia Bianchi, Giuseppe Danilo Norata, Federica M Marelli-Berg.
      
    DOI:  https://doi.org/10.1038/s42255-025-01256-3
  9. J Immunother Cancer. 2025 Feb 25. pii: e010153. [Epub ahead of print]13(2):
    Effector T cells under hypoxia have an altered transcriptome similar to tumor-stressed T cells found in non-responsive melanoma patients.
    Mate Z Nagy, Lourdes B Plaza-Rojas, Justin C Boucher, Elena Kostenko, Anna L Austin, Ahmad A Tarhini, Zhihua Chen, Dongliang Du, Awino Maureiq E Ojwang', Joshua Davis, Alyssa Obermayer, Katarzyna A Rejniak, Timothy I Shaw, Jose A Guevara-Patino.
       BACKGROUND: In the tumor microenvironment (TME), hypoxia stands as a significant factor that modulates immune responses, especially those driven by T cells. As T cell-based therapies often fail to work in solid tumors, this study aims to investigate the effects of hypoxia on T cell topo-distribution in the TME, gene expression association with T cell states, and clinical responses in melanoma.
    METHODS: To generate detailed information on tumor oxygenation and T cell accessibility, we used mathematical modeling of human melanoma tissue microarrays that incorporate oxygen supply from vessels, intratumoral diffusion, and cellular uptake. We created tumor maps and derived plots showing the fraction of CD4 and CD8 T cells against the distance to the nearest vessel and oxygen pressure. To assess their function and transcriptional changes caused by hypoxia, effector T cells were generated and cultured under hypoxia (0.5% oxygen) or normoxia (21% oxygen). The T cell hypoxia-transcriptional signature was compared against datasets from msigDB, iATLAS (clinical trials of melanoma patients treated with immune checkpoint inhibitors (ICIs)), ORIEN AVATAR (real-world melanoma patients treated with ICIs), and a single-cell atlas of tumor-infiltrating lymphocytes.
    RESULTS: We made three specific observations: (1) in melanoma T cells preferentially accumulated in oxygenated areas close to blood vessels (50-100 µm from the vasculature in the regions of high oxygen availability) but not in hypoxic areas far from blood vessels. (2) Our analysis confirmed that under hypoxia, T cell functions were significantly reduced compared with normoxic conditions and accompanied by a unique gene signature. Furthermore, this hypoxic gene signature was prevalent in resting and non-activated T cells. Notably and clinically relevant, the hypoxic T cell gene set was found to correlate with reduced overall survival and reduced progression-free survival in melanoma patients, which was more pronounced in non-responder patients undergoing ICI therapy. (3) Finally, compared with a single-cell atlas of tumor-infiltrating T cells, our hypoxia signature aligned with a population of cells at a state termed stress response state (TSTR).
    CONCLUSIONS: Our study highlights the critical role of hypoxia in shaping T cell distribution and its correlation with clinical outcomes in melanoma. We revealed a preferential accumulation of T cells in oxygenated areas. Moreover, hypoxic T cells develop a distinct hypoxic gene signature prevalent in resting, non-activated T cells and TSTR that was also associated with poorer outcomes, particularly pronounced among non-responders to ICIs.
    Keywords:  Gene expression profiling - GEP; Immune Checkpoint Inhibitor; Melanoma; Tumor infiltrating lymphocyte - TIL; Tumor microenvironment - TME
    DOI:  https://doi.org/10.1136/jitc-2024-010153
  10. Mol Cells. 2025 Feb 20. pii: S1016-8478(25)00022-6. [Epub ahead of print] 100198
    Metabolic Regulation by p53: Implications for Cancer Therapy.
    Ki Yeon Koo, Kwanho Moon, Hwa Seob Song, Min-Sik Lee.
      The tumor suppressor p53, long known for its roles in maintaining genomic integrity and suppressing tumorigenesis, has recently been recognized as a key regulator of cellular metabolism. Here, we review p53's emerging metabolic functions, highlighting its ability to orchestrate glucose, amino acid, and lipid metabolism. By promoting oxidative phosphorylation while inhibiting glycolysis and anabolic pathways, wild-type p53 counters metabolic reprogramming characteristic of cancer cells, such as the Warburg effect, and protects cells from mild cellular stresses. In contrast, mutant p53 disrupts these processes, fostering metabolic adaptations that support tumor progression. These findings pave the way for therapeutic approaches targeting p53-driven metabolic vulnerabilities in cancer.
    Keywords:  Cancer metabolism; Metabolic reprogramming; Tumor suppressor; p53 (TP53)
    DOI:  https://doi.org/10.1016/j.mocell.2025.100198
  11. RMD Open. 2025 Feb 26. pii: e005122. [Epub ahead of print]11(1):
    Association of peripheral CD8+ T cell activation with disease activity and treatment resistance in systemic lupus erythematosus.
    Yuya Fujita, Shingo Nakayamada, Satoshi Kubo, Yusuke Miyazaki, Koshiro Sonomoto, Hiroaki Tanaka, Yoshiya Tanaka.
       OBJECTIVE: Various immune-cell subsets intricately mediate the pathogenesis of systemic lupus erythematosus (SLE). However, the role of CD8+ T cells in SLE remains unclear. We investigated the proportions and characteristics of peripheral CD8+ T cells and their association with clinical manifestations of SLE.
    METHODS: We retrospectively enrolled 211 patients with SLE and 48 age- and sex-matched healthy controls (HCs). Peripheral CD8+ T cells were analysed using flow cytometry. The primary endpoint was the comparison of peripheral CD8+ T cell subset characteristics between patients and HCs.
    RESULTS: Patients with SLE (mean age, 42.3 years; women, 89% and mean disease duration, 112.8 months) had significantly higher proportions of naïve CD8+ T cells (CCR7+CD45RA+), CD8+ terminally differentiated effector memory cells (CCR7-CD45RA+) and activated CD8+ T cells (CD38+HLA-DR+) in peripheral blood mononuclear cells than HCs (p<0.001). Activated CD8 + T cells produced granzyme B and interferon-γ, which correlated with serum double-stranded (ds) DNA antibodies (rs=0.3146, p<0.0001) and 50% haemolytic unit of complement (rs=-0.3215, p=0.0003), and were significantly increased in patients with active systemic, renal or haematological involvement (p<0.05). Cluster analysis-based subgroup classification based on CD8 cell differentiation and activation revealed a group with high numbers of activated CD8+ T cells, highly active SLE and organ damage, including active nephritis and persistently high cell counts after a 24-week treatment, indicating treatment resistance (high anti-dsDNA antibody titres and high glucocorticoid doses).
    CONCLUSION: In SLE, greater proportions of highly cytotoxic and proinflammatory activated CD8+ T cells in peripheral blood-modulated disease activity, organ damage and residual treatment resistance, presenting a potential treatment target.
    Keywords:  Autoimmune Diseases; Lupus Erythematosus, Systemic; T-Lymphocytes
    DOI:  https://doi.org/10.1136/rmdopen-2024-005122
  12. Adv Sci (Weinh). 2025 Feb 27. e2411053
    CK2B Induces CD8+ T-Cell Exhaustion through HDAC8-Mediated Epigenetic Reprogramming to Limit the Efficacy of Anti-PD-1 Therapy in Non-Small-Cell Lung Cancer.
    Shaochuan Liu, Shiya Ma, Gen Liu, Lingjie Hou, Yong Guan, Liang Liu, Yuan Meng, Wenwen Yu, Ting Liu, Li Zhou, Zhiyong Yuan, Shuju Pang, Siyuan Zhang, Junyi Li, Xiubao Ren, Qian Sun.
      Anti-PD-1 therapy has left an indelible mark in the field of non-small-cell lung cancer (NSCLC) treatment; however, its efficacy is limited in clinical practice owing to differences in the degree of effector T-cell exhaustion. Casein kinase 2 (CK2) is a protein kinase that plays an important role in T-cell immunity. In this study, it is aimed to explore the potential of targeting CK2 and its regulatory subunit CK2B to prevent or reverse T-cell exhaustion, thereby enhancing the efficacy of anti-PD-1 therapy in NSCLC. In this study, it is found that CK2B expression is closely associated with T-cell exhaustion as well as the efficacy of anti-PD-1 therapy based on scRNA-seq and in vitro and in vivo experiments. Utilization of CK2 inhibitors or knockdown of CK2B expression can upregulate TBX21 expression through HDAC8-mediated epigenetic reprogramming, restoring the effector function of CD8+ T cells and enhancing the efficacy of anti-PD-1 therapy in NSCLC. These findings underscore CK2B as a promising target for overcoming the exhaustion of effector CD8+ T cells, thereby enhancing the efficacy of anti-PD-1 and adoptive cell therapies in NSCLC. Moreover, CK2B expression serves as a novel predictor of immunotherapy efficacy for NSCLC.
    Keywords:  CK2B; ICIs; NSCLC; T cell exhaustion; TME
    DOI:  https://doi.org/10.1002/advs.202411053
  13. bioRxiv. 2025 Feb 15. pii: 2025.02.10.637523. [Epub ahead of print]
    Functional memory T cells are derived from exhausted clones and expanded by checkpoint blockade.
    Colin J Raposo, Patrick K Yan, Andy Y Chen, Saba Majidi, Kamir J Hiam-Galvez, Ansuman T Satpathy.
      Immune checkpoint blockade can facilitate tumor clearance by T cells, resulting in long term patient survival. However, the capacity of exhausted CD8 + T cells (Tex), present during chronic antigen exposure, to form memory after antigen clearance remains unclear. Here, we performed longitudinal single cell RNA/T cell receptor sequencing and ATAC-sequencing on antigen-specific T cells after the clearance of chronic lymphocytic choriomeningitis virus (LCMV) infection. These data revealed the formation of a robust population of memory CD8 + T cells that transcriptionally, epigenetically, and functionally resemble central memory T cells (Tcm) that form after clearance of acute infection. To lineage trace the origin and memory recall response of Tex-derived memory clones, we utilized T cell receptor sequencing over the course of primary infection and rechallenge. We show that chronic Tcm are a clonally distinct lineage of Tex derived from progenitor exhausted cells, persist long-term in the absence of antigen, and undergo rapid clonal expansion during rechallenge. Finally, we demonstrate that αPD-L1 immune checkpoint blockade after chronic LCMV infection preferentially expands clones which form Tcm after clearance. Together, these data support the concept that chronically stimulated T cells form bona fide functional memory T cells through an analogous differentiation pathway to acutely stimulated T cells, which may have significant implications for enhancing immune memory to cancer through checkpoint blockade and vaccination.
    DOI:  https://doi.org/10.1101/2025.02.10.637523
  14. Nat Immunol. 2025 Feb 27.
    Autophagy repression in effector T lymphocytes redefines paradigms in T cell biology.
    Ruchi Saxena, You-Wen He.
      
    DOI:  https://doi.org/10.1038/s41590-025-02091-0
  15. Sci Rep. 2025 Feb 26. 15(1): 6844
    Single cell analysis identifies distinct CD4 + T cells associated with the pathobiology of pediatric obesity related asthma.
    David A Thompson, Yvonne B Wabara, Sarai Duran, Anna Reichenbach, Laura Chen, Kayla Collado, Changsuek Yon, John M Greally DMed, Deepa Rastogi.
      Pediatric obesity-related asthma is characterized by non-atopic T helper 1 (Th1) inflammation and steroid resistance. CDC42 upregulation in CD4 + T cells underlies Th1 inflammation but the CD4 + T cell subtype(s) with CDC42 upregulation and their contribution to steroid resistance are not known. Compared to healthy-weight asthma, obesity-alone and healthy-weight controls, single-cell transcriptomics of obese asthma CD4 + T cells revealed CDC42 upregulation in 3 clusters comprised of naïve and central memory T cells, which differed from the cluster enriched for Th1 responses that was comprised of effector T cells. NR3C1, coding for the glucocorticoid receptor, was downregulated, while genes coding for NLRP3 inflammasome were upregulated, in clusters with CDC42 upregulation and Th1 responses. Conserved genes in these clusters correlated with pulmonary function deficits in obese asthma. These findings suggest that several distinct CD4 + T cell subtypes are programmed in obese asthma for CDC42 upregulation, Th1 inflammation, and steroid resistance, and together contribute to the obese asthma phenotype.
    Keywords:  Asthma; CD4 + T cells; Children; Obesity
    DOI:  https://doi.org/10.1038/s41598-025-88423-4
  16. bioRxiv. 2025 Feb 16. pii: 2025.02.15.638423. [Epub ahead of print]
    Dietary cysteine enhances intestinal stemness via CD8 + T cell-derived IL-22.
    Fangtao Chi, Qiming Zhang, Jessica E S Shay, Johanna Ten Hoeve, Yin Yuan, Zhenning Yang, Heaji Shin, Sumeet Solanki, Yatrik M Shah, Judith Agudo, Ömer H Yilmaz.
      A critical question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues. The mammalian small intestine, a vital digestive organ that absorbs nutrients, is maintained by rapidly renewing Lgr5 + intestinal stem cells (ISCs) at the intestinal crypt base. While Lgr5 + ISCs drive intestinal adaptation by altering self-renewal and differentiation divisions in response to diverse diets such as high-fat diets and fasting regimens, little is known about how micronutrients, particularly amino acids, instruct Lgr5 + ISC fate decisions to control intestinal homeostasis and repair after injury. Here, we demonstrate that cysteine, an essential amino acid, enhances the ability of Lgr5 + ISCs to repair intestinal injury. Mechanistically, the effects of cysteine on ISC-driven repair are mediated by elevated IL-22 from intraepithelial CD8αβ + T cells. These findings highlight how coupled cysteine metabolism between ISCs and CD8 + T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.
    DOI:  https://doi.org/10.1101/2025.02.15.638423
  17. Cell Res. 2025 Feb 25.
    Mimicking the TCR immune synapse for improved CAR-T cell function.
    Tom Enbar, Li Tang.
      
    DOI:  https://doi.org/10.1038/s41422-025-01086-8
  18. Cell Rep. 2025 Feb 18. pii: S2211-1247(25)00058-0. [Epub ahead of print]44(2): 115287
    Glycolytic reprogramming shapes the histone acetylation profile of activated CD4+ T cells in juvenile idiopathic arthritis.
    Enric Mocholi, Edward Corrigan, Theo Chalkiadakis, Can Gulersonmez, Edwin Stigter, Bas Vastert, Jorg van Loosdregt, Stefan Prekovic, Paul J Coffer.
      Juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by accumulation of activated CD4+ T cells in the synovial fluid (SF) of affected joints. JIA CD4+ T cells exhibit a unique inflammation-associated epigenomic signature, but the underlying mechanisms remain unclear. We demonstrate that CD4+ T cells from JIA SF display heightened glycolysis upon activation and JIA-specific H3K27 acetylation, driving transcriptional reprogramming. Pharmacological inhibition of glycolysis altered the expression of genes associated with these acetylated regions. Healthy CD4+ T cells exposed to JIA SF exhibited increased glycolytic activity and transcriptomic changes marked by heightened histone 3 lysine 27 acetylation (H3K27ac) at JIA-specific genes. Elevated H3K27ac was dependent on glycolytic flux, while inhibiting glycolysis or pyruvate dehydrogenase (PDH) impaired transcription of SF-driven genes. These findings demonstrate a key role of glycolysis in JIA-specific gene expression, offering potential therapeutic targets for modulating inflammation in JIA.
    Keywords:  CP: Immunology; CP: Metabolism; T cells; autoimmune disease; glucose metabolism; histone acetylation; juvenile idiopathic arthritis; pyruvate dehydrogenase
    DOI:  https://doi.org/10.1016/j.celrep.2025.115287
  19. Nat Commun. 2025 Feb 26. 16(1): 2002
    CD301b+ dendritic cell-derived IL-2 dictates CD4+ T helper cell differentiation.
    Naoya Tatsumi, Jihad El-Fenej, Alejandro Davila-Pagan, Yosuke Kumamoto.
      T helper (Th) cell differentiation is fundamental to functional adaptive immunity. Different subsets of dendritic cells (DC) preferentially induce different types of Th cells, but the DC-derived mechanism for Th type 2 (Th2) differentiation is not fully understood. Here, we show that in mice, CD301b+ DCs, a major Th2-inducing DC subset, drive Th2 differentiation through cognate interaction by rapidly inducing IL-2 receptor signalling in CD4+ T cells. Mechanistically, CD40 engagement prompts IL-2 production selectively from CD301b+ DCs to maximize CD25 expression in CD4+ T cells, which instructs the Th2 fate decision, while simultaneously skewing CD4+ T cells away from the T follicular helper fate. Moreover, CD301b+ DCs utilize their own CD25 to facilitate directed action of IL-2 toward cognate CD4+ T cells, as genetic deletion of CD25 in CD301b+ DCs results in reduced IL-2-mediated signalling in antigen-specific CD4+ T cells and hence their Th2 differentiation. These results highlight the critical role of DC-intrinsic CD40-IL-2 axis in Th cell fate decision.
    DOI:  https://doi.org/10.1038/s41467-025-55916-9
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